Bound to fail: The flawed scientific foundations of agricultural genetic engineering (part 2)

The new understanding of “omnigenics” tells us GM food and crop technology is conceptually flawed – and genome editing won't change that, writes Dr Michael Antoniou

Many technologies, at the time of their inception, have appeared efficacious, safe, and generally a good idea, based on the science at the time. However, in a number of cases, a technology that was once deemed appropriate and desirable has later turned out to be not such a good idea after all. Not only has it failed to deliver on its promises, but it has given rise to environmental damage and negative health impacts. Such technologies have ended up being abandoned or tightly restricted.

There are many examples from history. Asbestos, DDT insecticides, leaded gasoline, and PCBs (polychlorinated biphenyls) in electrical goods were all once hailed as great innovations, but as we grew in our understanding of the mechanisms and complexities of nature’s functioning, we found they could have devastating effects on the health of humans and animals.

We continue to learn from our catastrophic mistakes, but only after serious damage has already occurred to health and the environment. In order to avoid such damage, we need to constantly review each technology from the perspective of the science from which it is derived. Transgenic and genome editing technologies are no exception.

So how does agricultural GM – including gene editing – fare when scrutinized from the perspective of the latest understanding of the field of molecular genetics, which studies the organization and control of genes?

Omnigenics

The development of new crop varieties by transgenic and gene editing is based on the notion that genes as isolated units of information that can be either manipulated within their host organism or moved from one species to another, with totally predictable outcomes.

But this viewpoint has been completely overturned by the new science of omnigenics, which teaches us that attempts to engineer complex traits (e.g. higher yield, drought tolerance, or disease resistance) into crops using transgenic methods and gene editing are destined to fail.

This is because no gene and/or its RNA or protein product works in isolation. These molecular components of life work as part of an integrated whole. The function of a given gene or its protein product therefore has to be viewed within the context of the whole genome and the whole organism. In other words, a gene cannot be seen just in terms of the information it carries for one or more proteins or RNA molecules, but in the context in which it exists and functions.

We now know that most genes will give rise to multiple RNAs and multiple protein products, each with their own specific function within the organism. Many functions are brought about not by one gene, but by many genes – and many proteins give rise to one characteristic. That’s why you can have far fewer genes than characteristics. Those characteristics are brought about not by single proteins but by multiple proteins working together, with any given protein potentially contributing to multiple functions.

Recently it has been discovered that complex traits have at their basis the integrated functioning of the entire genome of an organism. This concept is called omnigenics,[1,2] to reflect the fact that the entire complement of genes (the “genome”) is involved in delivering complex characteristics in the organism. In humans, such complex traits include both natural traits (e.g. height) and disease conditions (e.g. schizophrenia, rheumatoid arthritis, and Crohn’s disease).[1]

It’s possible that a set of “core” genes may be at the basis of complex traits, but omnigenics reveals that their function is augmented by all the other genes that are expressed in a given cell or tissue. Crucially, omnigenics suggests that genes in a cell should be viewed as a network.[1]

The omnigenic model of complex traits has been formulated based on observations in humans.[1] However, given the similarities between gene structure and function between animals and plants, it would not be surprising to find that complex traits in plants such as high yield potential, resistance to pests and diseases are also omnigenic in nature.

How does omnigenics relate to plant genetic engineering?

Transgenic technologies involve the introduction of a foreign gene unit into a new genetic context. This also includes the introduction of a gene between different varieties of the same crop, a process known as cisgenics. Advocates claim this can be done with totally predictable outcomes. However, in-depth molecular profiling analysis of transgenic plants shows that transgenic procedures invariably result in a spectrum of unpredicted alterations, not only in the function of the inserted foreign transgene but also of the plant's host genes. This in turn results in unintended changes in the plant's biochemistry.[3,4,5,6,7,8,9]

This matters because such unintended changes can make GM plants unexpectedly toxic or allergenic, perhaps accounting for at least some of the toxic effects found in animal feeding studies with GM crops[10] (other potential causes include the effects of the products of the intended GM trait, such as Bt toxins, and/or of the pesticides used with the GM crop[11]).

How unintended changes can happen in a GM plant

There are two main ways in which unpredictable and unexpected outcomes can arise in a GM plant:

1. The GM transformation process selects for transgene insertion events that are within sites of the plant host genome where other active genes are located. This creates a high risk of disrupting the balanced control of host gene networks, leading to undesirable changes in protein profiles and biochemistry.

2. As we’ve seen, our contemporary understanding of gene organisation and function teaches us that genes have evolved to function as networks within the genome of their native host organism. But transgenic technologies involve taking genes out of their natural context and placing them into a new genomic context, where the foreign transgene will become part of a new gene network. Thus, transgenesis will necessarily include an unpredictable aspect – once again resulting in undesirable changes in protein profiles and biochemistry.

Genome editing won't save the agricultural GMO model

At face value, certain applications of genome editing that involve alterations to one or a few host genes without the introduction of foreign genetic material would appear to avoid some of the conceptual flaws of transgenic technology. However, when it is borne in mind that the gene and its protein products are working as part of a network, this supposed advantage evaporates. That’s because even small changes in the activity of one component in the network can alter core biochemical pathways in the plant in unpredictable ways, in addition to the intended change.

Thus we can see that the treatment of genes as isolated units of information that can be manipulated predictably by either transgenic or genome editing methods is conceptually flawed, as it is out of step with the understanding that genes and their products function as part of highly sophisticated integrated networks of molecular activity.

Desirable complex traits of crops are an outcome of the entire physiological functioning of the plant, with omnigenics at its basis. So notions of improving characteristics such as yield from altering one or a few genes are destined to fail as they cannot bring about the required balanced entire system-wide improvement in the plant's functioning.

Taking into account the latest systems biology understanding of life’s molecular processes, it becomes clear that attempts to improve crops through enhancing or adding complex traits will only succeed if they use approaches that can bring about the required omnigenic functions. That’s why natural breeding, augmented where needed by genetic marker assisted selection, which preserves gene order and balanced control, has been strikingly successful in producing new crop varieties that are better yielding, more disease-resistant, and more robust in the face of climatic stressors.[12,13,14,15] Omnigenics also explains why transgenic methods have failed to enhance complex traits and why gene editing is destined to fail in this regard in the future.

References

1. Boyle EA, Li YI, Pritchard JK. An expanded view of complex traits: From polygenic to omnigenic. Cell. 2017;169(7):1177-1186. doi:10.1016/j.cell.2017.05.038

2. Greenwood V. ‘Omnigenic’ model suggests that all genes affect every complex trait. Quanta Mag. June 2018. https://www.quantamagazine.org/omnigenic-model-suggests-that-all-genes-affect-every-complex-trait-20180620/.

3. Agapito-Tenfen SZ, Guerra MP, Wikmark O-G, Nodari RO. Comparative proteomic analysis of genetically modified maize grown under different agroecosystems conditions in Brazil. Proteome Sci. 2013;11(1):46. doi:10.1186/1477-5956-11-46

4. Zolla L, Rinalducci S, Antonioli P, Righetti PG. Proteomics as a complementary tool for identifying unintended side effects occurring in transgenic maize seeds as a result of genetic modifications. J Proteome Res. 2008;7:1850-1861. doi:10.1021/pr0705082

5. Barbosa HS, Arruda SCC, Azevedo RA, Arruda MAZ. New insights on proteomics of transgenic soybean seeds: evaluation of differential expressions of enzymes and proteins. Anal Bioanal Chem. 2012;402(1):299-314. doi:10.1007/s00216-011-5409-1

6. Arruda SCC, Barbosa HS, Azevedo RA, Arruda MAZ. Comparative studies focusing on transgenic through cp4EPSPS gene and non-transgenic soybean plants: an analysis of protein species and enzymes. J Proteomics. 2013;93:107-116. doi:10.1016/j.jprot.2013.05.039

7. Lehesranta SJ, Davies HV, Shepherd LVT, et al. Comparison of tuber proteomes of potato varieties, landraces, and genetically modified lines. Plant Physiol. 2005;138(3):1690-1699. doi:10.1104/pp.105.060152

8. Gong CY, Li Q, Yu HT, Wang Z, Wang T. Proteomics insight into the biological safety of transgenic modification of rice as compared with conventional genetic breeding and spontaneous genotypic variation. J Proteome Res. 2012;11(5):3019-3029. doi:10.1021/pr300148w

9. Mesnage R, Agapito-Tenfen SZ, Vilperte V, et al. An integrated multi-omics analysis of the NK603 Roundup-tolerant GM maize reveals metabolism disturbances caused by the transformation process. Sci Rep. 2016;6:37855. doi:10.1038/srep37855

10. Krimsky S. An illusory consensus behind GMO health assessment. Sci Technol Hum Values. August 2015:0162243915598381. doi:10.1177/0162243915598381

11. Robinson C, Antoniou M, Fagan J. GMO Myths and Truths (4th Edition): A Citizen’s Guide to the Evidence on the Safety and Efficacy of Genetically Modified Crops and Foods, 4th Edition. Chelsea Green; 2018. https://www.amazon.com/GMO-Myths-Truths-Citizens-Genetically/dp/0993436722/ref=dp_ob_title_bk.

12. Gilbert N. Cross-bred crops get fit faster. Nat News. 2014;513(7518):292. doi:10.1038/513292a

13. Xu K, Xu X, Fukao T, et al. Sub1A is an ethylene-response-factor-like gene that confers submergence tolerance to rice. Nature. 2006;442:705-708. doi:10.1038/nature04920

14. Francia E, Tacconi G, Crosatti C, et al. Marker assisted selection in crop plants. Plant Cell Tissue Organ Cult. 2005;82(3):317-342. doi:10.1007/s11240-005-2387-z

15. GMWatch. Non-GM successes. gmwatch.org. http://www.gmwatch.org/index.php/articles/non-gm-successes. Published 2018.





Part 1 of this series of two articles is here: https://www.gmwatch.org/en/news/latest-news/18582