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From GMOs to GROs: Will Life Find a Way? (Repost)

This post was originally published on January 22 at the DNA Science Blog and is reposted with permission from the author.

Geneticist Ricki Lewis blogs from the cutting edge of genomics, including genetic testing, stem cells, gene therapy and more.

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A pair of papers in this week’s Nature introduces GROs — “genomically recoded organisms” — whose altered genetic code makes them require a synthetic amino acid to survive. Although this new type of biocontainment indeed keeps microorganisms from spreading to where they aren’t wanted, at least in a lab, I don’t think the approach is likely to convert many anti-GMO folks to biotech fans, based on my experience.

ROTTEN TOMATOES
Several years ago, I spoke about genetically modified organisms (GMOs) to a group of citizen environmentalists, my goal to explain the precise procedures behind the vague term “genetic engineering.” Alas, the audience rapidly nodded off as I distinguished a transgenic organism from a knockout. They didn’t believe my tale of the first GMO released to the environment, “ice-minus” bacteria, that were sprayed onto strawberry plants by Advanced Genetic Sciences in 1987 to block ice nucleation. Activists destroyed a treated strawberry patch, unaware that the GM bacteria actually lacked a gene, rather than harboring a foreign one.

Unlike these unadulterated tomatoes, the FlavrSavr failed not because it was genetically modified to have a long shelf life, but because it tasted bad.
Unlike these unadulterated tomatoes, the FlavrSavr failed not because it was genetically modified to have a long shelf life, but because it tasted bad.

The audience woke up, and became enraged, when I stated that traditional breeding is less precise than genetic manipulation. They yelled over my insistence that the same DNA triplets encode the same amino acids in all species. So unpleasant was the anti-science sentiment that I vowed never to speak about GMOs again.

My experience revealed that people fear GMOs – particularly plants – for a biological reason and an ethical reason:

#1: GMOs are perceived as not as safe to eat as unaltered vegetables and fruits.

#2 Any genetic manipulation beyond crossing and breeding is just wrong, an assault on nature.

Back then there was less concern about GMOs forcing reliance on certain herbicides and pesticides, and of “escape” to fields beyond where they’re intended to grow, two objections with which I agree.

TRIPLE-HEADED PURPLE MONSTERS
When I was in graduate school for genetics in the mid 1970s, the dawn of modern agricultural biotechnology, my mentor Thom Kaufman dubbed the unfounded fear of anything involving DNA the “triple-headed purple monster” mindset. It persists.

Even decades since we began regularly eating GMO crops, fear of their danger lingers. A January 17 article in the Washington Post proclaims “Over 80 Percent of Americans Support Mandatory Labels on Foods Containing DNA,” possibly the most idiotic headline of all time. Ever had a burger or banana that doesn’tcontain DNA? All organisms do. And all use the same genetic code.

Golden rice is genetically modified to produce beta-carotene, upping vitamin A level.
Golden rice is genetically modified to produce beta-carotene, upping vitamin A level.

I can’t fathom why people vehemently object to GM corn and soybeans, but not to vaccines and pharmaceuticals consisting of recombinant DNA translated into protein in non-human cells. Does anyone find offensive the candidate Ebola vaccines and drugs that include genes from different viruses grown in tobacco cells? “You Won’t Believe How They’re Growing the Ebola Vaccine” shouted another recent headline, above an article that repeatedly refers to “a bacteria” (that’s plural), and confuses bacteria with viruses. I wrote about producing recombinant DNA-derived proteins in tobacco plants in “Building a Better Tomato” in High Technology magazine, circa 1984.

The fact that 80% of those polled are demanding labels announcing the presence of DNA in their food confirms that the palpable fear and anger I felt years ago still simmers. And if that’s so, then the new studies about altering the genetic code may ignite a firestorm, despite the initial news emphasis on the fact that GROs have a genetic “safety lock.”

INTRODUCING GENETICALLY RECODED ORGANISMS
The Nature papers are a bit hard to follow, and require familiarity with the genetic code. It is the 64 possible mRNA triplets (codons) that are combinations of the four types of RNA bases (uracil, cytosine, adenine, and guanine), which are complementary to 64 types of DNA triplets. Of the 64 RNA codons, 61 encode any of 20 types of biological amino acids, and 3 mean “stop”: UAA, UAG, and UGA. A protein being synthesized along an mRNA molecule is complete when it encounters a stop codon. UAA, UAG, and UGA spell “stop” in all organisms, as well as in viruses. (Disclaimer: I have a UGA stop codon tee shirt.)

George Church of Personal Genome Project fame, who is the Robert Winthrop Professor of Genetics at Harvard Medical School, and colleagues report in the January 21 Nature that they replaced UAG “stop” codons in E. coli with UAA codons altered to bind and insert a “nonstandard amino acid” (NSAA) into a growing protein. An NSAA is not among the 20 that the natural genetic code specifies. The result is a GRO: a genomically recoded organism. It can’t survive without the NSAA.

“We now have the first example of genome-scale engineering rather than gene editing or genome copying. This is the most radically altered genome to date in terms of genome function. We have not only a new code, but also a new amino acid, and the organism is totally dependent on it,” said Dr. Church in a news release.

The genetic code. (NHGRI)
The genetic code. (NHGRI)

By swapping in the altered UAAs at many places in the bacterial genome, plus required tRNAs and “computationally redesigned” enzymes, protein synthesis incorporates the unnatural amino acids. As a result, DNA can’t move from cell to cell aboard viruses and other mobile DNA elements (horizontal gene transfer) or be replicated and passed to the next generation (vertical gene transfer),unless the NSAA is present.

Dr. Church calls the feat “irreversible, inescapable dependency.” All of this work is in very early stages and uses the standard E. coli and its T viruses, the stuff of classic molecular biology experiments from the 1960s and 1970s, and the microorganism in which many biological drugs are “pharmed.” It is a long way from being applied to fields of rhubarb.

GROs made their debut in a 2013 paper in Science from Dr. Church’s group, and were a candidate for the magazine’s “breakthrough of the year” in 2014. The 2013 paper describes the ability of GROs to resist viral infection, because they can’t be make viral proteins, as infected cells normally would. Viral infection can be disastrous for producing biopharmaceuticals or bioremediation agents.

In the second article on GROs in this week’s Nature, Farren J. Isaacs, an assistant professor of molecular, cell and developmental biology at Yale University, who did postdoctoral research in the Church lab, and colleagues describe retooling the UAG stop codons where they naturally occur in E. coli, but also introduce them into several essential genes. Their bacteria require two unnatural amino acids.

Dr. Isaacs and the Yale team also published an article with a headline I did like, “Multilayered genetic safeguards limit growth of microorganisms to defined environments,” in Nucleic Acids Research online January 7. They colorfully describe their multi-pronged approach as including “engineered riboregulators that tightly control expression of essential genes, and an engineered addiction module based on nucleases that cleaves the host genome.”

A NEW ROUTE TO BIOCONTAINMENT
In microbiological terms, a GRO is a “synthetic auxotroph.” Like bacteria before it genetically modified to resist an antibiotic or require a nutrient in order to survive, thereby providing a means of selection, the new breed of GROs depends on the NSAAs in the environment to make proteins, to stay alive and reproduce. A GRO can’t escape to where it isn’t wanted if it can’t get its NSAA.

In contrast to insecticide- or herbicide-resistant GMOs forcing reliance on a big company’s products, GROs work when something unnatural is not available in the environment. So they’d grow where the NSAA is, but not where it isn’t — if the technology ever extends beyond closed laboratory situations.

1024px-Jurassic_Park_4WD_and_dinosaur_at_Islands_of_Adventure-300x225Wherever GROs end up, the researchers hope the altered genetic code will enable them to circumvent nature’s ways of surviving. New detoxifying mutations won’t help, for there is no toxin. Nor can natural selection or even horizontal gene transfer remove the altered codons. And GROs can’t suck up useful nutrients from neighbors – they need those NSAAs. But as mathematician Ian Malcolm pointed out in Jurassic Park, where genetically altered dinosaurs ran amok, “nature finds a way.”

256px-X-Files_Dana_Scully_Cosplay-200x300Biocontainment based on altering the genetic code is an idea that was unimaginable back when such measures were first hammered out at the Asilomar conference on recombinant DNA held in 1975. In the 1990s, Dr. Dana (“I’m a scientist!”) Scully from the TV show The X-Files waxed melodramatic about a 5-base genetic code introduced by space aliens. It happens.

While GROs extend the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, the new papers are more proof-of-concept than practical, for now. None of the trillion E. coli that the Church lab grew over two weeks bolted. That’s “10,000 times better than the NIH recommendation for escape rate for genetically modified organisms,” Dr. Church said.

1000px-Mad_scientist.svg_-150x150THE MEDIA RESPONSE TO GROs

I eagerly awaited the media response to the reports on GROs, anticipating an uproar if the news aggregators went beyond the cautious news release to borrow phrases from the papers such as “whole organisms capable of sampling new evolutionary landscapes” and “reliance on synthetic metabolites.” Altering the genetic code is HUGE, a much more profound change than boosting beta carotene levels in rice or creating tomatoes with longer shelf lives, traits that result from single-gene changes.

The media coverage, so far, has been far less than I anticipated, with the usual suspects – the New York TimesScience Daily – doing a terrific job. But it wasn’t the stuff of CNN or the NBC evening news, and stories such as underinflated footballs, a cop singing along with Taylor Swift, and the arrest on corruption charges of the speaker of the New York State assembly, naturally got more coverage.

What would the anti-GMO organizations, places I don’t ordinarily visit since my traumatic lecture experience, say?

Greenpeace was concerned mainly with polar bears and whales. But GMO Awareness was apparently unaware that researchers had rewritten the genetic code and applied it to bacteria in a technology that could, someday, be used to reign in errant altered crops. The “breaking news” on their website is from October, and the featured story on their Facebook page concerns all-natural burgers, which I suspect in fact harbor some DNA.

It’s possible that the environmental groups do not yet comprehend the significance of what synthetic biology can do, or understand how it works. But maybe I’m wrong about that. Give it a few weeks.

Many questions remain, especially if GROs transition from initial roles in bioremediation and specialty chemicals and pharmaceuticals to food production. Will the NSAAs harm health if eaten or spread in the environment? Will the approach work for plants, which are so much more complex than E. coli?

As for me, I was recently asked again to speak about GMOs, in an adult education course next fall. I initially said no. But these two papers are so exciting that I’ve changed my mind.

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