Unpredictable genes

Genes are unpredictable.

A given gene may behave in many different ways, depending on the signals it is receiving from other parts of the genetic code, from other areas inside the cell, and from outside the cell. In this article, I want to outline the basic reasons it is wrong to say that a gene has a particular function, which is the basic assumption underlying much of commercial biotechnology (where the basis of their logic is something like this: if we take a gene "for X" and put it into organism "Y", then organism "Y" will now express the novel trait X indicated by that gene).

In a moment, I will explain some of the reasons why genes cannot by thought of in this way. I want to be clear that I am not proposing some radical and idiosyncratic version of the science of genetics. All of the points I raise can be found in basic undergrad textbooks (such as Gilbert, 2003). The problem we are facing is that the fact that genes are so complicated and adaptive is being ignored by companies seeking profits and by consumers who are being told a juvenile version of what genes are in an attempt to appease them. As long as geneticists remain coy and unwilling to express the overwhelmingly complex and interconnected nature of the genome in simple terms, influential people from Mark Lynas to Hilary Clinton are going to keep pushing a vision of the biosphere not based on reality. And with dire possible effects for those living within it.

But before I get into details, a very brief primer is needed for those of you who don't yet understand how genes do what they do...

A gene is a segment of DNA that "expresses" a certain protein product. Because proteins are the building blocks of bodies, genes are continually orchestrating the building and rebuilding of the body, in all its forms and functions. However, on their own, genes are inert molecules capable of doing very little. Throw a bunch of DNA into water and it just sits there. What turns genes into a source of information are the cells that they are found in, which have the context to read meaning into the genes. Without going into details, what happens is this: the information contained in a gene is "transcribed" into RNA. It is then edited down so it only includes relevant information, and then it is sent to the ribosome. The ribosome then "translates" the information in the RNA by producing a specific protein based on the coding of the RNA (a visual overview of the process can be seen here).

What makes genetics so interesting and so beautiful is not the machine-like consistency by which this process occurs, but the fact that it is open. It is responsive and subtle, adapting and re-adapting with incredible versatility to what comes along as the cell (and the organism it is a part of) lives its life. A gene does not simply enable the production of a protein, like a fixed blueprint of operating instructions for a giant factory. Instead, the information in the gene is itself fluid and dexterous, changing depending on how it gets read and re-read by the cell. Depending on the evolving circumstances of the cell, a gene is capable of getting turned off, turned on, getting stimulated to work more rapidly or more slowly, capable of collaborating (or ceasing collaboration) with other genes, and even of producing new types of protein. There is therefore a wonderful circularity and mutual dependence between the form and function of the genes and that of the organism. Scientists are trying to model the infinitesimal interactions that occur every second within and between the various genes in a cell but even with extremely powerful computers, they are a very long way off from understanding the diverse behaviours of genes and how adaptive they are to the environments they occur in.

I will discuss two major ways by which the information within genes is adapted or modified by the cell: chromatin remodelling and alternative splicing. Both ways enable an indefinite variety of possibilities for new behavior and ongoing sensitive response and learning on behalf of the lifeform.

Chromatin remodelling

In multicellular organisms such plants and animals, DNA is not naked and floating around on its own. It is found in a giant string of molecules known as chromatin. Chromatin is made up of DNA coiled around proteins called histones. Depending on how tightly the histones are packed together, the genes in the DNA can behave in very different ways.

For example, if the histones are very tightly packed (forming solenoids), genes in the DNA will usually be pinched off and therefore not expressed. Conversely, if the chromatin is stretched out, the genes will usually be exposed, allowing RNA polymerase to come in and initiate transcription.

However, there are also an infinite number of middle states between a closed off segment of chromatin and one that is open. If the chromatin chain is bent or folded in different configurations, different active genes can be put closer or further away from one another. Depending on the architecture of chromatin, the interactional possibilities between the various genes and regulatory sequences in the DNA changes. Much of these structural changes in chromatin are a result of alterations in the shape of the histone proteins that the DNA is coiled around (Baker, 2011). Histones have chemically reactive ends and are known to form bonds with over a hundred different molecules (for example, histones can be methylated, acetylated, phosphoylated, etc.). Each molecule that a histone reacts with will create a slightly different shape of that region of the chromatin, and thereby nudge interactive possibilities between the genes one way or another.

In organisms, chromatin is being adjusted and readjusted all the time in continuous adaptation to ongoing circumstances. As this occurs, individual genes and clusters of genes become expressed, attenuated or silenced at different rates, altering the nature of the gene products.

Alternative splicing

Plants and animals' genes also undergo what is called "alternative splicing" (Sharp & Richards). After a gene is transcribed into RNA, it is then edited to produce "messenger RNA". A gene is typically a very long molecule of DNA, only some parts of which are used for expression. The parts that are not used are cut out before the RNA is delivered to the ribosome. Alternative splicing refers to the fact that the same gene can be edited in different ways, producing many different variations of messenger RNA, each which will be expressed slightly differently by the ribosome. It is estimated that half of human genes produce RNA that is alternatively spliced in certain circumstances (Wu, Yuan, & Havlioglu, 2007), and some genes (such as those active in the nervous system) are even capable of hundreds or thousands of different alternative splicings.

What is kept and what is edited out from the gene to create the messenger RNA again depends on signals received from other parts of the DNA, from within the cell, and from outside the cell. This is therefore another means by which genes are continually readjusting how they behave in ongoing adaptation to their environments.

I'll stop here, but readers should know that there are many other mechanisms making genes supple and flexible. For example, sometimes a gene is transcribed into RNA but the RNA does not reach the ribosome for translation because it gets censored along the way (Gagnon, 1992; Gilbert, 2003). The RNA is prevented from leaving the nucleus, implying that there is a "selection process" culling undesired RNA before it becomes expressed. There are also "post-translational modifications" that occur to regulate the shape of the proteins produced by the ribosome (Seo & Lee, 2004).

As long as activists can understand chromatin remodelling and alternative splicing and communicate these concepts in the comment sections of articles on GMOs, we will be able to lodge better arguments against those quartering us in as ignorant and irrational.

Take home message
Genes are complex, unpredictable, and still poorly understood.
Genes in multicellular organisms do not usually have specific and unalterable behaviours throughout the lifespan of the organism. To say that they do is obviously misleading. To create technologies that are based on this assumption is dangerous. The novel genes inserted into a genetically modified organism will interact in unpredictable ways, especially through the ways their expression changes through chromatin remodelling and through alternative splicing. We do not have the technical or financial capacity to test for all these changes, in part because we don't really yet know the extent of what we are looking for. Because the ways in which the new gene interacts within its new cellular environment can cause it to produce alternative chromatin structures and perhaps alternative splicings, the gene is unlikely to behave in the ways it did in its original cellular environment. OMIC studies, which catalogue snapshots of the expression products of genes at various stages of their transcription and translation are available but not required by regulatory bodies and therefore not conducted by biotech companies.

However, they are occasionally conducted by researchers and published in peer-reviewed journals. Tellingly, they reveal some of the true complexity of the genome. Let me quote from a proteomic study conducted on MON 810, one of the most commonly planted GMO maize varieties, produced by Monsanto: "Approximately 100 total proteins resulted differentially modulated in the expression level as a consequence of the environmental influence (WT06 vs WT05), whereas 43 proteins resulted up- or down-regulated in transgenic seeds with respect to their controls (T06 vs WT06), which could be specifically related to the insertion of a single gene into a maize genome by particle bombardment. Transgenic seeds responded differentially to the same environment as compared to their respective isogenic controls, as a result of the genome rearrangement derived from gene insertion" (Zolla et al, 2008). Approximately 100 unpredictable expression effects revealed from a proteomic study conducted at two different times! One might imagine what proteomic studies undertaken at other times but additionally reveal, and also what other differences would be exposed were transcriptomic or metabolic studies also conducted.

Establishing "substantial equivalence", which implies that the GMO should not bear any special scrutiny compared with its non-GMO counterparts, is a far off pipe-dream.

The attempt to convince policy makers and consumers that genes are not incredibly complex and contingent things is painfully immoral. The public has the right and the need to understand something about this complexity before they are fed arguments as to why genetic engineering is "safe" or why citizens concerned about it are "wrong".

And geneticists should become confident in expressing this wondrous complexity to the public. Indeed, they have a duty to do so.


References

Baker, Monya. 2011. Making sense of chromatin. Nature 8:717-722.

Gagnon, M.L, L.M. Angerer, and R.C. Angerer. 1992. Posttranscriptional regulation of ectoderm-specific gene expression in early sea urchin embryos. Development 114:457-467.

Gilbert, Scott F. 2003. Developmental biology. 7th ed. Sunderland, MA: Sinauer Associates, Inc.

Seo J1, Lee KJ. 2004. Post-translational modifications and their biological functions: proteomic analysis and systematic approaches. J Biochem Mol Biol. 2004 Jan 31;37(1):35-44.

Wu, Jane Y., Liya Yuan, and Necat Havlioglu. 2007. Alternatively spliced genes. In Genomics and genetics, edited by R. A. Meyers. Weinheim, Germany: Wiley-VCH.

Zolla, L., Rinalducci, S., Antonioli, P., & Righetti, G. (2008) Proteomics as a complementary tool for identifying unintended side effects occurring in transgenic maize seeds as a result of genetic modifications. Journal of Proteome Research, 7(5), p. 1850-1861