Three key risks

A cell biologist's warning
Thanks to Professor David Schubert for this contribution.
(If you find the article difficult to follow, there is a less technical version at the end.)

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:
  • That introducing the same gene into two different types of cells can produce two very distinct protein molecules
  • The recent observations that the introduction of any gene, be it from different or the same species, always significantly changes overall gene expression and therefore the phenotype of the recipient cell
  • and 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.

FIRST

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.

SECOND

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 pattern 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.

THE OUTCOME?
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.

ADDRESSING THE CONCERNS
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 to 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.

Professor David Schubert
Cellular Neurobiology Laboratory
The Salk Institute for Biological Studies
P.O. Box 85800
San Diego, CA 92186-5800
USA
JULY 2002

HERE’S A LESS TECHNICAL VERSION
Professor Schubert suggests three key risks inherent in any genetic transformation of a plant or animal.

FIRST
A single gene can, in fact, produce many different substances under different circumstances.
Plants and animals are composed of many different types of cell which can have very different structures and entirely different functions: compare, for example, the obvious differences between a plant’s leaves and its roots, or, animal skin and muscle. In any individual, the genes inside all these different cells are identical, but the cells turn out differently because their genes produce different active proteins.

As an example of this, Professor Schubert describes how, after the basic chemical chain structure of a protein has been made in a cell, it can be altered by the addition of a variety of other substances, which will alter its function. He cites a protein produced by the same gene in human liver and nerve cells which is altered by the addition of two different sugars and makes the cells stick together differently.

This means that a single foreign gene added to an individual’s cells with the intention that it produces a single desired protein (such as the Bt toxin inserted in maize to kill pests) could in fact produce a variety of other proteins potentially harmful to the consumer.

SECOND
The activity of all the natural genes in a cell is altered by inserting one novel gene.

If any additional gene (even one from the same species) is introduced into a cell, all the original genes in that cell will act differently as a result. This will cause the structure and function of the cell to be altered. As an example of this Professor Schubert describes an experiment in which a slightly modified gene similar to a gene already present was introduced into human cells and resulted in a change in activity level of five per cent of the total genes there.

In another example, even the introduction of a ‘marker’ gene, used only to identify the GM cells, caused a change in activity level of three per cent of the natural genes.

This makes nonsense of statements which imply that GM is safe because only one gene is being inserted. Cells maintain their very special individual structure and function because all the genes in them are tailoring their activity appropriately and acting precisely together. Upsetting the activity of one part will potentially alter the whole.

The danger is that disturbing the ability of the natural genes to work in harmony with each other, will cause novel substances to arise which could be harmful to the consumer.

THIRD
Novel substances can interfere with other chemical reactions in the cell. Genes work together to create sequences of chemicals reactions within the cell. Introducing novel genes which produce their own novel sequences could interfere with the natural reactions.

As an example, Professor Schubert describes how tiny concentrations of chemicals related to vitamin A can damage development in growing mammals, such as humans. A plant with genes added to produce vitamin A might also produce small but very harmful amounts of a related chemical.

THE OUTCOME
The above GM side effects are unpredictable and could lead to immediate poisoning which would be readily recognised. However, cancer-causing effects, indirect chemical interference, or harmful interactions with other foods would take decades to detect or might never be recognised.

ADDRESSING THE CONCERNS
The only reasonable solution is to test all GM plants destined for human consumption for poisonous and cancer-causing agents before they are marketed.

OUR COMMENT
Bear in mind one further implication of the three risks identified by Professor Schubert. 
If a GM plant variety has been thoroughly tested and found to be free from harmful by-products, this DOESN’T MEAN that another plant of the same species which has gained the novel gene through genetic pollution will be safe because the interactions described above will be different.