Substantial Equivalence Via Metabolomics

The principle of Substantial Equivalence (SE) has been crucial in the debate whether genetically engineered (GE) plants might contain unexpected and potentially undesirable changes in their overall metabolite composition, on account of GE.   In course of time, two opposing positions have emerged, on the adequacy of SE in determining the safety of GE products as food and feed. 

SE has been a routine and stringent criterion of the US Food and Drug Administration (FDA) in ensuring the safety of foods and drugs marketed in the US. Efforts are made to demonstrate that a GE variety and its products are ‘substantially equivalent’ to its conventional variety and its products, but for the trnsgenes in the new variety and the consequent expected products of the transgenes.      Once SE is established, the FDA requires no further regulatory review.   Under the ‘provision for voluntary consultation’, the US biotech companies seek SE certification by FDA, of all GE varieties and their products they intend to market.   The product developers submit to the FDA, voluminous dossiers on the safety and risk analysis of the GE varieties and their products developed by them.   These data are usually confined to the comparative study of proteins, carbohydrates and other components of nutritional significance.   The focus is on determining whether the new GE varieties and their products are toxic or allergenic.   If some GE products contain miniscule quantities of a few additional components that are a) broken down during food processing or digestion or b) if they occur below acceptable independently determined threshold levels, the products are regarded as  'Generally Recognized As Safe' (GRAS).  

Products from transgenic soybean, tomato, corn, cotton, etc., on the US markets have been tested extensively, much more than any conventional foods, and judged SE to their conventional counterparts.   The US citizens who have been consuming GE food products are a living testimony of their safety.  

Nevertheless, the official consensus of the European Union (EU) is that, SE should only be used to guide to inform safety assessments. The EU safety regulations, based on this premise, are so stringent that they raised doubts whether any GE product will at all qualify to be considered safe.    

The Codex Alimentarius Commission (CAC) is the international organization established in 1963, jointly by the FAO and WHO, under the Food Standards Programme.   Comprised of 165 member countries, the CAC also sees SE as a starting point in the regulatory process rather than an end point.

Recent research by Catchpole Gareth and 11 others, published in the Proceedings of the US National Academy of Sciences (PNAS, September 26, 2005, 26/9/095), used the sophisticated but complex procedures of Metabolomics, an area of Bioinformatics, to establish SE between GE and conventional potatoes.

Biological problem solving through Bioinformatics (computational biology), employs the resources of sophisticated and sensitive chemical profiling, applied mathematics, informatics, statistics, and computer science.   Till recently, the major efforts in bioinformatics have been related to unravelling component sequences, structure and function of nucleic acids (Genomics) and proteins (Proteomics), in order to predict function from structure and vice versa.
Metabolomics is a ‘finger print’ study metabolomes, which are the whole set of chemical entities of a cell, tissue, organ, organisms, or species.   The metabolome includes proteins, RNA, DNA and various substrates, the molecules enzymes act upon.   Metabolomics gives a ‘snap shot’ of the physiology and its products in a cell.     The study of metabolomes, resulting from stress or disease is metabonomics.
Gareth’s team made a comprehensive comparison of total metabolites (the intermediates and products of metabolism), in field-grown GE and conventional potato tubers.   Their metabolome "fingerprinting" studies provide for a detailed profiling of metabolites where significant differences are suspected.   They have demonstrated that, apart from targeted changes, the GM potatoes in the study were substantially equivalent to traditional cultivars.   
The minor differences that were found between the GE and the non-GE varieties were of the same kind and magnitude of such differences among the non-GE varieties, that occur on account of natural variation in gene expression.   And these differences are not significant in the context of the safety of the GE potatoes for human consumption.
In the debate on SE it is often held that,

a)      the focus of SE has been well known nutritionally significant components, occurring in considerably large quantities,

b)      the studies employed routine food safety testing methods which are not sensitive enough to detect all components and not detailed total critical analyses, and

c)      that more sophisticated and deep analytical approaches may reveal chemical compounds hither to unexpected and unknown, which may make the GE products unsafe for human consumption.  
Further, the US SE data were generated not by independent entities but by the product developers themselves and largely remained in the private domain, not easy for others to access for evaluation.  
The work of Gareth’s team is safe from all such criticism.