Last month, a group of Australian scientists published a warning to the citizens of the country and of the world who collectively gobble up some $34 billion annually of its agricultural exports. The warning concerned the safety of a new type of wheat. As Australia’s number-one export, a $6-billion annual industry, and the most-consumed grain locally, wheat is of the utmost importance to the country. A serious safety risk from wheat – a mad wheat disease of sorts – would have disastrous effects for the country and for its customers. Which is why the alarm bells are being rung over a new variety of wheat being ushered toward production by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) of Australia. In a sense, the crop is little different than the wide variety of modern genetically modified foods. A sequence of the plant’s genes has been turned off to change the wheat’s natural behavior a bit, to make it more commercially viable (hardier, higher yielding, slower decaying, etc.). Franken-Wheat? What’s really different this time – and what has Professor Jack Heinemann of the University of Canterbury, NZ, and Associate Professor Judy Carman, a biochemist at Flinders University in Australia, holding press conferences to garner attention to the subject – is the technique employed to effectuate the genetic change. It doesn’t modify the genes of the wheat plants in question; instead, a specialized gene blocker interferes with the natural action of the genes. The process at issue, dubbed RNA interference or RNAi for short, has been a hotbed of research activity ever since the Nobel Prize-winning 1997 research paper that described the process. It is one of a number of so-called “antisense” technologies that help suppress natural genetic expression and provide a mechanism for suppressing undesirable genetic behaviors. RNAi’s appeal is simple: it can potentially provide a temporary, reversible off switch for genes. Unlike most other genetic modification techniques, it doesn’t require making permanent changes to the underlying genome of the target. Instead, specialized siRNAs – chemical DNA blockers based on the same mechanism our own bodies use to temporarily turn genes on and off as needed – are delivered into the target organism and act to block the messages cells use to express a particular gene. When those messages meet with their chemical opposites, they turn inert. And when all of the siRNA is used up, the effect wears off. The new wheat is in early-stage field trials (i.e., it’s been planted to grow somewhere, but has not yet been tested for human consumption), part of a multi-year process on its way to potential approval and not unlike the rigorous process many drugs go through. The researchers responsible are using RNAi to turn down the production of glycogen. They are targeting the production of the wheat branching enzyme which, if suppressed, would result in a much lower starch level for the wheat. The result would be a grain with a lower glycemic index – i.e., healthier wheat. This is a noble goal. However, Professors Heinemann and Carman warn, there’s a risk that the gene silencing done to these plants might make its way into humans and wreak havoc on our bodies. In their press conference and subsequent papers, they describe the possibility that the siRNA molecules – which are pretty hardy little chemicals and not easily gotten rid of – could wind up interacting with our RNA. If their theories prove true, the results might be as bad as mimicking glycogen storage disease IV, a super-rare genetic disorder which almost always leads to early childhood death. “Franken-Wheat Causes Massive Deaths from Liver Failure!” Now that is potentially headline-grabbing stuff. Unfortunately, much of it is mere speculation at this point, albeit rooted in scientific expertise on the subject. What they’ve produced is a series of opinion papers – not scientific research nor empirical data to prove that what they suspect might happen, actually does. They point to the possibilities that could happen if a number of criteria are met: If the siRNAs remain in the wheat in transferrable form, in large quantities, when the grain makes it to your plate. And… If the siRNA molecules interfere with the somewhat different but largely similar human branching enzyme as well. Then the result might be symptoms similar to such a condition, on some scale or another, anywhere from completely unnoticeable to highly impactful. They further postulate that if the same effect is seen in animals, it could result in devastating ecological impact. Dead bugs and dead wild animals. Luckily for us, as potential consumers of these foods, all of these are easily testable theories. And this is precisely the type of data the lengthy approval process is meant to look at. Opinion papers like this – while not to be confused with conclusions resulting from solid research – are a critically important part of the scientific process, challenging researchers to provide hard data on areas that other experts suspect could be overlooked. Professors Carman and Heinemann provide a very important public good in challenging the strength of the due-diligence process for RNAi’s use in agriculture, an incomplete subject we continue to discover more about every day. However, we’ll have to wait until the data come back on this particular experiment – among thousands of similar ones being conducted at government labs, universities, and in the research facilities of commercial agribusinesses like Monsanto and Cargill – to know if this wheat variety would in fact result in a dietary apocalypse. That’s a notion many anti-genetically modified organism (GMO) pundits seem to have latched onto following the press conference the professors held. But if the history of modern agriculture can teach us anything, it’s that far more aggressive forms of GMO foods appear to have had a huge net positive effect on the global economy and our lives. Not only have they not killed us, in many ways GMO foods have been responsible for the massive increases in public health and quality of life around the world. The Roots of the GMO Food Debate The debate over genetically modified (GM) food is a heated one. Few contest that we are working in somewhat murky waters when it comes to genetically modified anything, human or plant alike. At issue, really, is the question of whether we are prepared to use the technologies we’ve discovered. In other words, are we the equivalent of a herd of monkeys armed with bazookas, unable to comprehend the sheer destructive power we possess yet perfectly capable of pulling the trigger? Or do we simply face the same type of daunting intellectual challenge as those who discovered fire, electricity, or even penicillin, at a time when the tools to fully understand how they worked had not yet been conceived of? In all of those cases, we were able to probe, study, and learn the mysteries of these incredible discoveries over time. Sure, there were certainly costly mistakes along the way. But we were also able to make great use of them to advance civilization long before we fully understood how they worked at a scientific level. Much is the same in the study and practical use of GM foods. While the fundamentals of DNA have been well understood for decades, we are still in the process of uncovering many of the inner workings of what is arguably the single most advanced form of programming humans have ever encountered. It is still very much a rapidly evolving science to this day. For example, in the 1990s, an idea known simply as “gene therapy” – really a generalized term for a host of new-at-the-time experimental techniques that share the simple characteristic of permanently modifying the genetic make-up of an organism – was all the rage in medical study. Two decades on, it’s hardly ever spoken of. That’s because the great majority of attempted disease therapies from genetic modification failed, with many resulting in terrible side effects and even death for the patients who underwent the treatments. Its use in the early days, of course, was limited almost exclusively to some of the world’s most debilitating, genetically rooted diseases. Still – whether in their zeal to use a fledgling tool to cure a dreadful malady or in selfish, hurried desire to be recognized among the pioneers of what they thought would be the very future of medicine – doctors chose to move forward at a dangerous pace with gene therapy. In one famous case, and somewhat typical of the times, University of Pennsylvania physicians enrolled a sick 18-year-old boy with a liver mutation into a trial for a gene therapy that was known to have resulted in the deaths of some of the monkeys it had just been tested on. The treatment resulted in the young man’s death a few days later, and the lengthy investigation that followed resulted in serious accusations of what can only be called “cowboy medicine.” Not one of science’s prouder moments, to be sure. But could GM foods be following the same dangerous path? After all, the first GM foods made their way to market during the same time period. The 1980s saw large-scale genetic-science research and experimentation from agricultural companies, producing everything from antibiotic-resistant tobacco to pesticide-hardy corn. After much debate and study, in 1994 the FDA gave approval to the first GM food to be sold in the United States: the ironically named Flavr Savr tomato, with its delayed ripening genes which made it an ideal candidate for sitting for days or weeks on grocery store shelves. Ever since, there has been a seeming rush of modified foods into the marketplace. Modern GM foods include soybeans, corn, cotton, canola, sugar beets, and a number of squash and greens varieties, as well as products made from them. One of the most prevalent modifications is to make plants glyphosate-resistant, or in common terms, “Roundup Ready.” This yields varieties that are able to stand up to much heavier doses of the herbicide Roundup, which is used to keep weeds and other pest plants from damaging large monoculture fields, thereby reducing costs and lowering risks. In total it is estimated that modern GM crops have grown to become a $12 billion annual business since their commercialization in 1994, according to the International Service for the Acquisition of Agri-biotech Applications (ISAAA). Over 15 million farms around the world are reported to have grown GM crops, and their popularity increases every year. They’ve brought huge improvements in shelf life, pathogen and other stress resistance, and even added nutritional benefits. For instance, yellow rice – which was the first approved crop with an entirely new genetic pathway added artificially – provides beta-carotene to a large population of people around the world who otherwise struggle to find enough in their diets. However, the race for horticulturalists to the genetic table in the past few decades – what could be described accurately as the transgenic generation of research – has by no means been our first experiment with the genetic manipulation of food. In fact, if anything, it is a more deliberate, well studied, and careful advance than those that came before it. A VERY Brief History of Genetically Modified Food Some proponents of GMO foods are quick to point out that humans have been modifying foods at the genetic level since the dawn of agriculture itself. We crossbreed plants with each other to produce hybrids (can I interest you in a boysenberry?). And of course, we select our crops for breeding from those with the most desirable traits, effectively encouraging genetic mutations that would have otherwise resulted in natural failure, if not helped along by human hands. Corn as we know it, for example, would never have survived in nature without our help in breeding it. Using that as a justification for genetic meddling, however, is like saying we know that NASCAR drivers don’t need seatbelts because kids have been building soapbox racers without them for years. Nature, had the mix not been near ideal to begin with, would have prevented such crossbreeding. Despite Hollywood’s desires, one can’t simply crossbreed a human and a fly, or even a bee and a mosquito, for that matter – their genetics are too different to naturally mix. And even if it did somehow occur, if it did not make for a hardier result, then natural selection would have quickly kicked in. No, I am talking about real, scientific genetic mucking – the kind we imagined would result in the destruction of the world from giant killer tomatoes or man-eating cockroaches in our B-grade science-fiction films. Radiation mutants. Enterprising agrarians have been blasting plants with radiation of all sorts ever since we started messing around with atomic science at the dawn of the 20th century. In the 1920s, just when Einstein and Fermi were getting in their grooves, Dr. Lewis Stadler at the University of Missouri was busy blasting barley seeds with X-rays – research that would usher in a frenzy of mutation breeding to follow. With the advent of nuclear technology from the war effort, X-rays expanded into atomic radiation, with the use of gamma rays leading the pack. The United States even actively encouraged the practice for decades, through a program dubbed “Atoms for Peace” that proliferated nuclear technology throughout various parts of the private sector in a hope that it would improve the lives of many. And it did. Today, thousands of agricultural varieties we take for granted – including, according to a 2007 New York Times feature on the practice, “rice, wheat, barley, pears, peas, cotton, peppermint, sunflowers, peanuts, grapefruit, sesame, bananas, cassava and sorghum” – are a direct result of mutation breeding. They would not be classified as GM foods, in the sense that we did not use modern transgenic techniques to make them, but they are genetically altered nonetheless, to the same or greater degree than most modern GMO strains. Unlike modern GM foods – which are often closely protected by patents and armies of lawyers to ensure the inventing companies reap maximum profits from their use – the overwhelming majority of the original generations of radiation-mutated plant varieties came out of academic and government sponsored research, and thus were provided free and clear for farmers to use without restriction. With the chemical revolution of the mid-20th century, radiation-based mutations were followed by the use of chemical agents like the methyl sulfate family of mutagens. And after that, the crudest forms of organic genetic manipulation came into use, such as the uses of transposons, highly repetitive strands of DNA discovered in 1948 that can be used like biological duct tape to cover whole sections the genome. These modified crops stood up better to pests, lessened famines, reduced reliance on pesticides, and most of all enabled farmers to increase their effective yields. Coupled with the development of commercial machinery like tractors and harvesters, the rise of mutagenic breeding resulted in an agricultural revolution of a magnitude few truly appreciate. In the late 1800s, the overwhelming majority of global populations lived in rural areas, and most people spent their lives in agrarian pursuits. From subsistence farmers to small commercial operations, the majority of the population of every country, the US included, was employed in agriculture. Today, less than 2% of the American population (legal and illegal combined) works in farming of any kind. Yet we have more than enough food to feed all of our people, and a surplus to export to more densely populated nations like China and India. The result is that a sizable percentage of the world’s plant crops today – the ones on top of which much of the modern-era GMO experiments are done – are already genetic mutants. Hence the slippery slope that serves as the foundation of the resistance from regulators over the labeling of GM food products. Where do you draw the line on what to label? And frankly, how do you even know for sure, following the Wild-West days of blasting everything that could grow with some form or another of radiation, what plants are truly virgin DNA? The world’s public is largely unaware that many of the foods they eat today – far more than those targeted by anti-GMO protestors and labeling advocates – are genetically modified. Yet we don’t seem to be dying off in large numbers, like the anti-RNAi researchers project will happen. In fact, global lifespans have increased dramatically across the board in the last century. The Rise of Careful The science of GM food has advanced considerably since the dark ages of the 1920s. Previous versions of mutation breeding were akin to trying to fix a pair of eyeglasses with a sledgehammer – messy and imprecise, with rare positive results. And the outputs of those experiments were often foisted upon a public without any knowledge or understanding of what they were consuming. Modern-day GM foods are produced with a much more precise toolset, which means less unintended collateral damage. Of course it also opens up a veritable Pandora’s box of new possibilities (glow-in-the-dark corn, anyone?) and with it a whole host of potential new risks. Like any sufficiently powerful technology, such as the radiation and harsh chemicals used in prior generations of mutation breeding, without careful control over its use, the results can be devastating. This fact is only outweighed by the massive improvements over the prior, messier generation of techniques. And thus, regulatory regimes from the FDA to CSIRO to the European Food Safety Authority (EFSA) are taking increasing steps to ensure that GM foods are thoroughly tested long before they come to market. In many ways, the tests are far more rigorous than those that prescription drugs undergo, as the target population is not sick and in need of urgent care, and for which side effects can be tolerated. This is why a great many of the proposed GM foods of the last 20 years, including the controversial “suicide seeds” meant to protect the intellectual property of the large GM seed producers like Monsanto (which bought out Calgene, the inventor of that Flavr Savr tomato, and is now the 800-lb. gorilla of the GM food business), were never allowed to market. Still, with the 15 years from 1996 to 2011 seeing a 96-fold increase in the amount of land dedicated to growing GM crops and the incalculable success of the generations of pre-transgenic mutants before them, scientists and corporations are still in a mad sprint to find the next billion-dollar GM blockbuster. In doing so they are seeking tools that make the discovery of such breakthroughs faster and more reliable. With RNAi, they may just have found one such tool. If it holds true to its laboratory promises, its benefits will be obvious from all sides. Unlike previous generations of GMO, RNAi-treated crops do not need to be permanently modified. This means that mutations which outlive their usefulness, like resistance to a plague which is eradicated, do not need to live on forever. This allows companies to be more responsive, and potentially provides a big relief to consumers concerned about the implications of eating foods with permanent genetic modifications. The simple science of creating RNAi molecules is also attractive to people who develop these new agricultural products, as once a messenger RNA is identified, there is a precise formula to tell you exactly how to shut it off, potentially saving millions or even billions of dollars that would be spent in the research lab trying to figure out exactly how to affect a particular genetic process. And with the temporary nature of the technique, both the farmers and the Monsantos of the world can breathe easily over the huge intellectual-property questions of how to deal with genetically altered seeds. Not to mention the questions of natural spread of strains between farms who might not want GMO crops in their midst. Instead of needing to engineer in complex genetic functions to ensure progeny don’t pass down enhancements for free and that black markets in GMO seeds don’t flourish, the economic equation becomes as simple as fertilizer: use it or don’t. While RNAi is not a panacea for GMO scientists – it serves as an off switch, but cannot add new traits nor even turn on dormant ones – the dawn of antisense techniques is likely to mean an even further acceleration of the science of genetic meddling in agriculture. Its tools are more precise even than many of the most recent permanent genetic-modification methods. And the temporary nature of the technique – the ability to apply it selectively as needed versus breeding it directly into plants which may not benefit from the change decades on – is sure to please farmers, and maybe even consumers as well. That is, unless the scientists in Australia are proven correct, and the siRNAs used in experiments today make their way into humans and affect the same genetic functions in us as they do in the plants. The science behind their assertions still needs a great deal of testing. Much of their assertion defies the basic understanding of how siRNA molecules are delivered – an incredibly difficult and delicate process that has been the subject of hundreds of millions of dollars of research thus far, and still remains, thanks to our incredible immune systems, a daunting challenge in front of one of the most promising forms of medicine (and now of farming too). Still, their perspective is important food for thought… and likely fuel for much more debate to come. After all, even if you must label your products as containing GMO-derived ingredients, does that apply if you just treated an otherwise normal plant with a temporary, consumable, genetic on or off switch? In theory, the plant which ends up on your plate is once again genetically no different than the one which would have been on your plate had no siRNAs been used during its formative stages. One thing is sure: the GMO food train left the station nearly a century ago and is now a very big business that will continue to grow and to innovate, using RNAi and other techniques to come. The Casey Extraordinary Technology team has been tracking the leading lights of the RNAi medical industry for some time. Recently, one of our small biotech upstarts struck a potentially massive, exclusive deal with an agricultural giant to seed its own RNAi research program. 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