As a cell biologist I am very much discouraged by the content of the ongoing debate about introducing genetically modified (GM) plants into the marketplace. While the voiced concerns usually center around irrational emotional arguments on the one hand, and the erroneous concept that genetic engineering is just like plant breeding on the other, I believe that the three issues which should be of most concern on the basis of established science receive little or no discussion. These are: 1. that introducing the same gene into 2 different types of cells can produce two very distinct protein molecules; 2. the recent observations that the introduction of any gene, be it from a different or the same species, always significantly changes overall gene expression and therefore the phenotype of the recipient cell; and 3. the possibility that enzymatic pathways introduced to synthesize small molecules such as vitamins can interact with endogenous pathways to produce novel molecules. The potential consequence of all of these perturbations could be the production of biomolecules that are either toxic or carcinogenic, and there is no _a priori_ way of predicting the outcome. I will give a few examples and then argue why GM food is not a safe alternative. In addition to their primary sequence of amino acids, the structure and biological activity of proteins can be modified by the addition of molecules such as phosphate, sulfate, sugars or lipids. The nature of these secondary modifications is totally dependent upon the cell type in which they are expressed. For example, if a protein involved in the cause of Alzheimer's disease, the beta amyloid precursor protein, is expressed in liver cells it contains covalently-attached chondroitin sulfate carbohydrate, while the identical gene expressed in brain nerve cells contains a much simpler sugar. This is because each cell type expresses a unique repertoire of enzymes capable of modifying proteins after they are synthesized. Once modified, the biological activity of the molecule may be changed. In the case of the beta-amyloid precursor protein, the adhesive properties of the cells are changed, but there is, at our current state of knowledge, no way of knowing the biological effects of these modifications. The second concern is the potential for inducing the synthesis of poisonous or toxic compounds following the introduction of a foreign gene. These observations are clearly at odds with the individuals who imply that everything is fine because they are simply introducing one gene. In fact, the introduction of a single gene invariably alters the gene expression pattern of the whole cell and each cell of the individual or plant responds differently. One recently published example is the transfection of a receptor gene into human cells. In this case, the gene was a closely related isoform of an endogenously expressed gene. The pattern of gene expression was monitored using gene chip technology, and the mRNA levels of 5% of the genes was significantly upregulated or downregulated. Similarly, the simple introduction of a bacterial enzyme used for growth selection of transfected cells changes the expression of 3% of the genes. While these types of unpredicted changes in gene expression are very real, they have not received much attention outside the community of the DNA chip users. Furthermore, they are not unexpected. The maintenance of a specific cell phenotype is a very precise balancing act of gene regulation, and any perturbation is going to change the overall patterns of gene expression. The problem, like that of secondary modifications, is that there is currently no way to predict the resultant changes in protein synthesis. Third, the introduction of genes for a new enzymatic pathway into plants could lead to the synthesis of totally novel or unexpected products via the interaction with endogenous pathways. Some of the products could be toxic. For example, retinoic acid (vitamin A) and derivatives of retinoic acid are used in many signaling events that control mammalian development. Since these compounds are soluble and work at ultralow concentrations, a GM plant making vitamin A may also produce retinoic acid derivatives which act as agonists or antagonists in these pathways, resulting in abnormal embryonic development. Given the fact that genetically modified plants are going to make proteins in different amounts and perhaps totally new proteins than their parental species, what are the potential outcomes? A worst case scenario could be that an introduced bacterial toxin is modified to make it toxic to humans. Direct toxicity may be rapidly detected once the product enters the marketplace, but carcinogenic activity or toxicity caused by interaction with other foods would take decades to detect, if ever. The same outcomes would be predicted for the production of toxins or carcinogens via indirect changes in gene expression. Finally, if the above problems are real, what can be done to address these concerns? The issue of secondary modification could be addressed by continual monitoring of the introduced gene product by mass spectroscopy. The problem is that some secondary modifications, like phosphorylation or sulfation can be lost during purification. However, the best, and to me the only reasonable solution, is to require all genetically engineered plant products for human consumption be tested for toxicity and carcinogenicity before they are marketed. These safety criteria are required for many chemicals and all drugs, and the magnitude of harm caused by a widely consumed toxic food would be much greater than that of any single drug.:
