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THE INABILITY TO PREDICT AND CONTROL THE OUTCOME OF GENE MANIPULATIONS The inability of biotechnologists to fully control and predict the outcome of genetic modifications of food organisms is due to three factors: the complexity of the recipient organism; the ten- dency of recombinant DNA manipulations to induce mutations at random locations within the genome of the recipient organism; and the ambiguity of, and cell-type specificity of, regulatory genetic information. food-producing organisms insert not one but several copies of a gene into the genome of the recipient organism. Thus, multiple random mutagenic events may occur, greatly increasing the prob- ability of damaging some gene important to food quality. The risks related to manipulating the genomes of food-produc- ing organisms are inherent in the mechanisms by which recombi- nant DNA techniques bring about genetic change. These risks cannot be discounted by pointing to the "FlavrSavr" tomato (the first genetically engineered crop to be commercialised) and saying that there have been no problems with it and therefore other trans- genics will probably be safe, too. Each transgenic food-producing organism will undergo different mutagenic events and respond to the genetic information introduced into it differently, leading to the range of unexpected alterations described above. Therefore, there is no scientifically valid justification for such extrapolations. 1. Biological complexity leads to the inability to control or predict the effects of recombinant DNA manipulations. An important contributor to the unpredictability of genetic engi- neering is the complexity of the recipient organism. The struc- tures and functions of even the simplest single-celled micro- organism are sufficiently complex that developers cannot take all components of the system into account when they consider the impact of a given genetic alteration. In such a situation, surprises are inevitable, and many of those surprises will not be advantageous. The mechanisms by which genetic manipulations can lead to increased allergenicity and toxi- city, described below, provide examples of such surprises. ~-o -~- . ~ ~ components of the system into account when they consider the 3. Ambiguities of Genetic Information. impact of a given genetic alteration. Genes contain two distinct kinds of information: structural and In such a situation, surprises are inevitable, and many of those —_ regulatory. Structural information specifies the amino acid surprises will not be advantageous. The mechanisms by which sequence of proteins and consists of the genetic code, which was genetic manipulations can lead to increased allergenicity and toxi- elucidated in the 1960s. With a few exceptions, this code is iden- city, described below, provide examples of such surprises. tical for all terrestrial organisms. Thus, the structural information contained in a given piece of DNA 2. Mutations through Recombinant is predictable. DNA Manipulations. However, the story is quite dif- The second source of uncertainty A A AF ferent for regulatory information. regarding the effects of recombinant | *** genetic alterations have a finite Transcription, translation, repli- DNA manipulations stems from the probability of altering the cation, recombination and other extremely crude nature of current gene . . processes involving DNA and transfer techniques. The genetic informa- properties of the organism, such RNA are controlled by regulatory tion introduced into the organism may be that the properties of the food information encoded in DNA or precisely defined in sequence, but it is A . 7 RNA sequences. inserted at random into the genome of the derived from it will be hazardous The regulatory decoder is recipient organism. Each insertional to health. much more complex and diverse than the structural code. Furthermore, it is different in dif- ferent organisms, and is even dif- ferent in different cell types of event is in fact a random mutagenic event. Stated another way, gene transfer as it is commonly done is a mutagenic process that can disrupt any of the processes in which DNA and RNA par- the same organism. For instance, there are many examples in the ticipate. The sites at which such mutations occur will be random. molecular biological literature in which recombinant genes, char- Therefore, there is no way to predict which gene or regulatory acterised in one cell type, are expressed at 100-fold or even 1,000- processes will be disrupted as a result of gene transfer-induced fold higher levels in another cell type from the same organism. mutagenesis. Such differences cannot be predicted simply by knowing the By inactivating or altering the expression of genes encoding nucleic acid sequence of a recombinant gene. The only way to enzymes that catalyse important biosynthetic processes, muta- know is to gather empirical information—by actually introducing genic events could alter the allergenicity of a food or make it the gene into the second cell type and examining the result. toxic, as described in detail below. These mutagenic events could If this is the case for different cell types within a single organ- also alter the nutritional qualities of a food. Furthermore, by ism, the level of unpredictability will certainly be as great or altering regulatory sequences present normally in the recipient greater for cross-species transfers of the kind commonly carried organism's genome, the same variety of regulatory sequence-relat- out in agricultural genetic engineering. ed problems described below could be generated. The underlying mechanism involved in the ‘reading’ of regula- It should be pointed out that with most gene transfer methods tory information is well understood. Regulatory proteins exist in used in eukaryotes, this mutational process will occur not just the cell, each of which is capable of scanning DNA (or RNA) sometimes but every time a recombinant gene is inserted into the molecules. Each can recognise and bind to a single, specific genome of an organism. Each such insertional event disrupts nucleic acid motif. That binding reaction triggers biochemical some native DNA sequence. Many such disruptions will, fortu- events leading to modulation of a process such as transcription, nately, be silent or inconsequential. However, there is a finite translation, replication, recombination, etc. In any particular cell, chance that one of these will alter the structure or function of the a given sequence can influence one of these processes only if the organism in a manner that significantly influences the properties protein that recognises that sequence is also present. Since differ- of the foodstuff derived from it. That is, genetic alterations have a ent regulatory proteins are expressed in different cell types and in finite probability of altering the properties of the organism, such different species, a given DNA sequence will function as a regula- that the properties of the food derived from it will be hazardous to tory signal only in some cell types and some species, and not in health. In most cases, the procedures used in modification of others. Our knowledge of the 'regulatory code' is extremely to health. NEXUS - 19 FEBRUARY - MARCH 1997