Why GMOs Can Never be Safe

The new genetics tells us that organisms need to engage in natural genetic modification in order to survive; artificial genetic modification interferes fundamentally with the natural process, and it is well-nigh impossible to avoid doing so Dr. Mae-Wan Ho

This report is based on invited lectures delivered in GMOs and Food Safety International Forum 2013, 9-10 July 2013, Yunnan University of Finance Economics, Kunming, Yunnan; and 13 July 2013, Gloria Plaza Hotel Beijing, China.

Power point presentation available for download here

From ivory tower academic to science activist

I was an ivory-tower academic who had rejected mechanistic biology from the start, and kept changing fields in search of the meaning of life, until just over 20 years ago, when some of the world’s top physicists and chemists inspired me (see [1] Quantum Jazz Biology, interview) to invent a new quantum physics of the organism [2] The Rainbow and the Worm, The Physics of Organisms. Soon after that, I met remarkable people like Vandana Shiva and Chee Yokeling of the Third World Network, who taught me just how important science is in shaping people’s lives and how crucial to get the science right. To me, science is the most intimate knowledge of nature that is beautiful beyond compare; it is also reliable knowledge that enables us to live sustainably with nature, and I have dedicated my life since to defending and promoting that science.

The greatest danger of GM

One main theme of my book [3] Genetic Engineering Dream or Nightmare, the Brave New World of Bad Science and Big Business - first published by Vandana in 1997 and by Third World Network in 1998 ahead of the commercial publications and translations – is to elaborate what I consider to be the greatest danger of genetic modification: its being misguided by the ideology of genetic determinism.

The rationale and impetus for genetic engineering and genetic modification is the ‘central dogma’ of molecular biology that assumes DNA (deoxyribose nucleic acid) carries all the instructions for making an organism. Individual ‘genetic messages’ in DNA faithfully copied into RNA (ribosenucleic acid),  is then translated into a protein via a genetic code; the protein determining a particular trait, such as herbicide tolerance, or insect resistance; one gene, one character.  If it were really as simple as that, genetic modification would work perfectly. Unfortunately this simplistic picture is an illusion.

Instead of linear causal chains leading from DNA to RNA to protein and downstream biological functions, complex feed-forward and feed-back cycles interconnect organism and environment at all levels to mark and change RNA and DNA down the generations (Figure 1).  Molecular geneticists have coined the term ‘fluid genome’ by 1980. The fluid genome belongs in the organic quantum paradigm of interconnectedness, as Vandana says. Organisms work by intercommunication at every level, and not by control. Control belongs in the static mechanistic paradigm of the central dogma.

Figure 1   The new genetics of the fluid genome versus the central dogma

In order to survive, the organism needs to engage in natural genetic modification in real time, an exquisitely precise molecular dance of life in which RNA and DNA respond to, and participate fully in ‘downstream’ biological functions.  That is why organisms and ecosystems are particularly vulnerable to the crude, artificial GM RNA and DNA created by human genetic engineers. It is also why genetic modification can probably never be safe.

More importantly, the human organism shapes its own development and evolutionary future; that is why we must take responsible action to ban all environmental releases of GMOs now. Not only have GM crops failed to deliver on the many false promises, they are unsafe for health and the environment [4] (Ban GMOs Now, I-SIS publication), and obstructing the shift to sustainable non-GM agriculture that’s productive, resilient and health-promoting (see [5] Food Futures Now *Organic *Sustainable *Fossil Fuel Free , I-SIS/TWN publication), and precisely what we need in times of climate change.

Big difference between natural and artificial genetic modification

A  GMO (genetically modified organism) is simply an organism with synthetic genetic material inserted into its genome.  It is made in the laboratory with sterile techniques, which also means without sex. The genome is all the genetic material of an organism (apart from those in mitochondria and chloroplasts), a copy of which is in practically every cell; and in cells with a nucleus, the genome is enclosed within the nucleus, organised into chromosomes.  Each chromosome unwinds into long threads of chromatin, consisting of proteins coating the double helix DNA. Strip off the proteins, and the DNA can be chopped and changed and recombined in test tubes, copied, amplified, and transferred into any organism, and that is what artificial genetic engineering and genetic modification involves (Figure 2).

Figure 2   What is involved in making a GMO (see text)

A transgene (Fig. 2) is a unit of the synthetic genetic material transferred into cells to make a GMO that expresses the required protein. It consists of a signal for starting the transcription, the promoter, the coding sequence determining the amino acid sequence of the protein and the signal for ending, the terminator. The three parts of the transgene are typically from different sources and variously modified with synthetic sequences that bear no relationship to any natural DNA; and this applies to each of the parts as well. More than one transgenes are usually included in a GM construct, most often, an antibiotic resistance gene to help select for cells that have taken up the GM construct.

There are big differences between natural genetic modification done by organisms themselves and the artificial genetic modification done by ‘genetic engineers’ in the lab (Table 1). Natural genetic modification is precise and predictable. It happens in the right place, at the right time without damaging the genome, and as appropriate to the organisms as a whole in relation to its environment. In contrast, artificial genetic modification is crude, imprecise, unpredictable and uncontrollable. The artificially created GM constructs have to be smuggled in by (disarmed) pathogenic bacteria and viruses that infect the cells, or otherwise forced into the cells by gene guns or electric shocks. The artificial constructs get scrambled in the process and could land anywhere in the genome, scrambling and damaging the genome in the process. Aggressive promoters are used essentially to force foreign genes to be expressed out of context.

Table 1   Contrasting natural and artificial genetic modification
Natural genetic modification	Artificial genetic modification
Precisely negotiated by the organism as a whole	Crude, imprecise, unpredictable uncontrollable
Takes place at the right place & time without damaging the genome	Forced into cells with no control over where & in what forms the artificial constructs land with much collateral damage to the genome
Appropriate to the organism as a whole in relation to its environment	Aggressive promoters force foreign genes to be expressed out of context

There is, therefore, nothing natural about artificial genetic modification done in the lab.

• It lacks the precision and finesse of the natural process
• It is greatly enhanced gene transfer without sex, also called horizontal gene transfer
• GM constructs are designed to cross species barriers and to jump into genomes with aggressive promoters to force expression of transgenes out of context
• It enables genes to be transferred between species that would never have exchanged genes otherwise
• GM constructs tend to be unstable – with weak joints from being cobbled together from different sources as well as well-known break points associated with promoters and terminators -  and hence, more prone to further horizontal gene transfer after it has integrated into the genome

Consequently, all the signs are that genetic modification is inherently hazardous.

GM inherently hazardous

Reliable evidence obtained by scientist independent of the biotech industry fully corroborates real life experiences of farmers in the field from different parts of the world (hitherto dismissed by the scientific establishment as “anecdotal evidence”): GM feed and other exposures to GMOs invariably cause harm, regardless of the species of animal, the GM crop, or the genes and constructs involved. A full list is presented in our report [4], and it includes the most horrendous cases of excess deaths, birth defects, infertility, tumours and cancers (some of which will be presented by other scientists at this conference). The inevitable conclusion one comes to is that genetic modification is inherently hazardous, on account of the new genetics of the fluid and responsive genome. I list the categories of hazards in Table 2.

Table 2   Hazards of GMOs

1. Uncontrollable, unpredictable impacts on safety due to the genetic modification process* Scrambling the host genome* Widespread mutations* Inactivating genes* Activating genes* Creating new transcripts (RNAs) including those with regulatory functions* Creating new proteins Creating new metabolites or increasing metabolite to toxic levels* Activating dormant viruses* Creating new viruses by recombination of viral genes in GM insert with those in the host genome*

2. Toxicity of transgene protein(s) introduced (intentionally or otherwise) Transgene protein toxic* Transgene protein allergenic or immunogenic* Trangenic protein becoming allergenic or immunogenic due to processing* Unintended protein created by sequence inserted may be toxic or immunogenic

3. Effects due to the GM insert and its instability* Genetic rearrangement with further unpredictable effects* Horizontal gene transfer and recombination* Spreading antibiotic and drug resistance* Creating new viruses and bacteria that cause diseases Creating mutations in genomes of cells to which the GM insert integrate including those associated with cancer*

4. Toxicity of herbicides used with herbicide tolerant GM crops*

*Documented in scientific literature

Although the weight of evidence against the safety of GMOs is overwhelming, we are still largely in the dark as to the precise nature of the hazard(s) associated with different GMOs. Toxicity has been found for transgene products such as the Bt proteins from different strains of the soil bacteria Bacillus thuringiensis expressed in many GM crops,  while the multiple toxicities, endocrine disrupting propensity and carcinogenicity of glyphosate herbicides, heavily used with glyphosate tolerant GM crops, are no longer in doubt as reviewed in detail in our report [4]. There remains a range of hazards not so easily identified without dedicated research, even though evidence exists for most, if not all of them in the scientific literature. These are due to the unpredictability and uncontrollable nature of the genetic modification process itself (Table 2, category 1), which can activate or inactivate genes, scramble genomes, create new proteins, new nucleic acids, new metabolites, and others due to the transgenic DNA and its instability (Table 2 category 3), of horizontal gene transfer - the direct transfer of DNA into the genomes of cells - from the GMO to all other species that come into contact with the GMO.

Transgene instability & the illegality of GMOs

Since the 1990s, some of us have raised the possibility of unintended secondary horizontal gene transfer from GMOs released into the environment with detailed reviews and reports, many of which were sent to our regulators (see [4] for references). At first the regulators and GM proponents denied that horizontal gene transfer could happen at all, or the probability is so tiny as to be practically zero. Later, when it became clear from molecular genetic analyses that rampant horizontal gene transfer has taken place in the course of evolution and in recent times, they said horizontal gene transfer is a natural process and therefore no need to worry; anti-GM is just anti-science.

Horizontal gene transfer is indeed a natural process, normally under the control of the organism itself, which is why GM DNA is such a threat. On account of its increase propensity for horizontal gene transfer, GM DNA can take over the natural process to gain access to the organisms’ genome regardless of whether it is appropriate or not.

The increased propensity of GM DNA for horizontal gene transfer translates into the instability of transgenic lines. Transgenes not only get silenced (no longer expressed) in successive generations, but can also become rearranged or lost. Transgene instability is an open secret buried under the permissive regulatory carpet. Independent scientists in Europe first discover that all commercially approved and hence risk assessed and molecularly characterized GM inserts were different from what was reported by the companies. Since then, at least one of them, MON 810, was found to have rearranged again, and now there is a substantial literature on transgene instability (see [4]). This is not at all surprising, given that GM DNA is unstable, and the foreign DNA does not really fit in with the whole organism, which is why transgenes tend to be silenced or lost.

The implications of transgene instability are far reaching. Transgene instability makes a mockery of the risk assessment process, because any change in transgene expression, or worse, rearrangement or movement of the transgenic DNA insert(s) would create another transgenic plant different from the one that was characterized and risk assessed. And it matters little how thoroughly the original characterization and risk assessment may have been done. The legislature should take note: unstable transgenic lines are illegal. Not only should they not be still growing commercially, they are also strictly ineligible for patent protection.

Horizontal gene transfer from GMOs does happen and often

There is now no doubt that horizontal gene transfer from GMOs does happen. For the first time, a proper study was carried out in 2012 by scientists in China, who found ampicillin resistance bacteria in all 6 of China’s major rivers [6]. Sequencing confirmed that the gene is a synthetic version derived from the laboratory, and different from the wild type. It is the same as the version present in numerous GM crops released in China commercially or in field trials (see [7] GM Antibiotic Resistance in China's Rivers, SiS 57). The researchers suggested that horizontal gene transfer of genetically engineered plasmids may underlie the rise in antibiotic resistance in animals as well as humans.

In the only authenticated feeding trial of GM food on human volunteers carried out by scientists in the UK, the complete transgene DNA of Roundup Ready soybean was recovered from the colostomy bag in 6 out of 7 subjects after a single meal, at levels up to 3.7 % of intake. In 3 subjects, about 1 to 3 per million bacteria cultured from the contents of the colostomy bag were positive for the GM soybean transgene, showing that horizontal transfer of GM DNA had occurred; but no bacteria were found to have taken up the vastly more abundant non-transgenic soybean DNA. This is direct evidence that GM DNA has a much greater propensity for horizontal gene transfer, as I have maintained from the start [3].

It is now clear that horizontal transfer of GM DNA does happen, and very often. Evidence dating from the early 1990s indicates that ingested DNA in food and feed can indeed survive the digestive tract, and pass through the intestinal wall to enter the bloodstream. The digestive tract is a hotspot for horizontal gene transfer to and between bacteria and other microorganisms.

Recent evidence obtained with direct detection methods indicates that horizontal transfer of GM DNA is routinely underestimated, largely because the overwhelming majority of bacteria in the environment and particularly in the gut cannot be cultured. GM DNA transfers at high frequencies to bacteria and fungi on the surfaces of leaves and stems, helped by the plant wound hormones; and the soil around the plant roots (rhizosphere) is also a hotspot for horizontal gene transfer. Higher organisms including human beings are even more susceptible to horizontal gene transfer than bacteria, because unlike bacteria, which require sequence homology (similarity) for incorporation into the genome, higher organisms do not.

To make things worse, DNA and RNA are now known to be actively secreted by living cells in a nucleic acid intercommunication system; the nucleic acids are taken up by target cells to modify gene expression and may be integrated into the cell’s genome. The profile of the circulating nucleic acids changes according to states of health and disease. Cancer cells use the system to spread cancer around the body. This nucleic acid intercom leaves the body very vulnerable to GM DNA and RNA, because they can take over the system for horizontal gene transfer into cells of all tissues including germ cells.

One type of nucleic acids, the microRNAs (miRNAs), are specifically involved in gene silencing via a vastly complex and flexible process that changes according to the environmental context. Consequently, GMOs based on miRNAs have many potentially adverse off-target effects, which are radically unpredictable and uncontrollable [8] RNA Interference “Complex and Flexible” & Beyond Control, SiS 59).

Dangers of GM DNA and its horizontal transfer

What are the dangers of GM DNA from horizontal gene transfer?  Horizontal transfer of DNA into the genome of cells per se is harmful, but there are extra dangers from the genes or genetic signals in the GM DNA, and also from the vector used in delivering the transgene(s).

· GM DNA jumping into genomes  cause ‘insertion mutagenesis’ that can lead to cancer, or activate dormant viruses that cause diseases

· GM DNA often contains antibiotic resistance genes that can spread to pathogenic bacteria and make infections untreatable

· Horizontal transfer and recombination of GM DNA is a main route for creating new viruses & bacteria that cause diseases

· The CaMV 35S promoter, widely used in GM DNA for crops on the mistaken assumption that it works only in plants, actually works in practically all living species including bacteria and human cells; recent research also suggests it may enhance the multiplication of disease-associated viruses including HIV (human immunodeficiency virus). In addition, the promoter overlaps with a virus gene (gene VI) that inhibits gene-silencing, a crucial host defence against viral infections

· The Agrobacterium vector, most widely used for creating GM plants is found to transfer genes also to fungi and human cells, and to share genetic signals for gene transfer with common bacteria in the environment. In addition, the Agrobacterium bacteria and its gene transfer vector tend to remain in the GM crops created, constituting a ready route for horizontal gene transfer to all organisms that come into contact with the GMO or the soil on which GM crops are grown. In 2008, Agrobacterium was linked to the outbreak of Morgellons disease. The Centers for Disease Control in the US launched an investigation but failed to investigate the link to Agrobacterium.

The full story of what I have tried to convey is in the final chapter of our report [4] with more than 140 references for that chapter alone. I hope this convinces you to avoid GMOs as far as possible; and especially don’t let your children eat GM food.  We must ban further environmental releases while we recall and destroy existing ones. We can’t wait for our central governments, or the European Union, or the United Nations to do that. Ban them from your home, your local community, your fields, your village, your town, your city, your province. The governments will follow your lead.

It is often said that GMOs once released is uncontrollable. But nothing is really controllable in the new fluid-genome organic paradigm. Fortunately, organisms are resilient, and able to heal themselves, and ecosystems are like organisms [2]; once we stop releasing GMOs and stop insulting them with other practices of industrial monoculture, ecosystems can recover and regain their health and productivity under sustainable agro-ecological farming [5]. That’s all the more reason for us to stop GMOs now; before it is really too late.

Article first published 22/07/13

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References

1. Riley D, McCraty R, and Snyder S. Quantum jazz biology, Mae-Wan Ho, Pioneering work in understanding life. Science in Society 47, 4-9, 2010.
2. Ho MW. The Rainbow and the Worm, the Physics of Organisms, World Scientific, 1993, 2nd edition, 1998, 3rd enlarged edition, 2008, Singapore and London, https://www.i-sis.org.uk/rnbwwrm.php
3. Ho MW. Genetic Engineering Dream of Nightmare? The Brave New World of Bad Science and Big Business, Third World Network, Gateway Books, MacMillan, Continuum, Penang, Malaysia, Bath, UK, Dublin, Ireland, New York, USA, 1998, 1999, 2007 (reprint with extended Introduction). http://www.i-sis.orucg.uk/genet.php
4. Ho MW and Sirinathsinghji E. Ban GMOs Now, I-SIS Report, 2013, https://www.i-sis.org.uk/Ban_GMOs_Now_-_Special_I-SIS_Report.php
5. Ho MW, Burcher S, Lim LC, Cummins J. et al. Food Futures Now, Organic, Sustainable, Fossil Fuel Free, I-SIS/TWN, London/Penang, 2008. https://www.i-sis.org.uk/foodFutures.php
6. Chen J, Jin M, Qiu ZG, Guo C, Chen ZL, Shen ZQ, Wang XW, Li JW. A survey of drug resistance bla genes originating from synthetic plasmid vectors in six Chinese rivers. Environmental Science & Technology 2012, 46, 13448-54.
7. Sirinathsinghji E. GM antibiotic resistance in China’s rivers. Science in Society 57, 6-7, 2013.
8. Ho MW. RNA interference “complex and flexible” & beyond control. Science In Society 59 (to appear).