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Natural versus artificial genetic engineering

Mae-Wan Ho - Institute of Science in Society and Department of Biological Sciences, Open University, Walton Hall, Milton Keynes, MK7 6AA, UK

Dear friends,

The following reply to Trewavas and Leaver's long correspondence in Nature was rejected on ground that "no new point" was raised. I am posting it again in case T&L's fallacious argument is taken seriously by anyone.

Sir - Trewavas and Leaver (1) claim that genetic engineering is no different from the natural processes that have been occurring throughout evolution. Moreover, they argue that this is supported by what I wrote in my book (2).

Perhaps they have not read the whole book, for I explain, especially in the second edition, that while artificial genetic engineering is uncontrollable, random and unpredictable, natural genetic engineering is quite precise and repeatable because it is regulated by the organism as a whole (3). This regulatory system has evolved over hundreds of millions of years. Under steady state conditions, proof-reading, DNA-repair and other mechanisms ensure that the DNA remains constant and stable. But predictable rearrangements, amplifications, deletions and mutations may also take place during normal development and in response to certain environmental conditions.

In contrast, DNA polymerase reactions in the test-tube are prone to error. Artificial transformation gives unpredictable, unrepeatable results and the transgenic lines obtained are often unstable. Trewavas and Leaver assume that lethal insertions [for the plant] are selected out, while potentially innocuous insertions [for consumers] are detected by ‘substantial equivalence’. But current risk assessment hardly addresses the unpredictability of the process or the stability of transgenic lines (4).

There are two main reasons for the unpredictability and instability of artificial genetic engineering. First, foreign DNA is broken down and inactivated by restriction mechanisms in the host cells. Second, the transgenic constructs -made up of DNA originating from many different sources - are structurally unstable (5).

Several expression-cassettes are usually stacked in series, each cassette consisting of a gene with a promoter (as well as terminator). The promoter is often taken from a virus in order to make the gene over-express. The stacked cassettes are, in turn, spliced into a vector, the most widely used being the T-DNA of Agrobacterium; and it is this whole construct which is intended for integration. But unpredictable deletions, rearrangements and repeats are invariably present in the actual insert. Transgenic instability often persists after the insertion event (6). The constitutive over-expression of transgenes placed under viral promoters may be one cause of gene-silencing (7), and recombination hotspots may be another.

The borders of T-DNA are recombination hotspots, as is the 3’ end of the 35S promoter from the cauliflower mosaic virus (CaMV) (8), which is used in practically all transgenic plants currently released. Recombination hotspots are expected to increase the likelihood of secondary mobility and horizontal gene transfer (9). Secondary mobility within the host genome may result in rearrangements and other effects that could drastically alter the agronomic and other properties of the transgenic line.

That plant genomes, like animal genomes, harbour retrotransposons, relict retroviruses and pararetroviruses (10) is no reason for complacency. These sequences have existed for millions of years in the genome, and are probably no longer harmful, either to the plant itself or to other organisms interacting with it. However, should they recombine with the CaMV promoter (or modules thereof) in the transgenic DNA, live viruses may well be regenerated. The transgenic DNA may also be mobilized by these relict elements.

Horizontal gene transfer could spread transgenic DNA to unrelated species, in principle, to all species that interact with the transgenic plant, including bacteria and viruses in all environments, and animals that feed on the plant. Chief among the potential dangers are the spread of antibiotic resistance marker genes, the creation of new viruses and bacteria that cause diseases, and insertion mutagenesis, including cancer in mammalian cells. These potentials should be addressed by empirical investigations instead of bland reassurances of ‘substantial equivalence’.


1. Trewavas, A. and Leaver, C. Nature 403, 12 (2000).

2. Ho, M.W. Genetic Engineering Dream or Nightmare? Gateway Books, Bath (1998); 2nd ed., Gill & Macmillan, Dublin (1999).

3. See Shapiro, J. Trends in Genetics 13, 98-104 (1997).

4. See Ho, M.W. and Steinbrecher, R. Environmental and Nutritional Interactions 2, 51-84 (1998).

5. The structural instability of artificial vectors made by joining DNA from widely different sources is a text-book topic. See Old, R.W. and Primrose, S.B. Principles of Gene Manipulation (fifth edition), Blackwell, Oxford (1994); also Prazeres, D.M.F. et al. Tibtech 17, 169174 (1999).

6. See Srivastava, V., Anderson, O.D. and Ow, D.W. Proc. Nat. Acad. Sci. USA 96, 11117-11121 (1999).

7. See Finnegan, J. and McElroy, D. Bio/Technology 12, 883-888 (1994).

8. See Kohli, A., et al. The Plant Journal 17, 591-601 (1999).

9. See Ho, M.W., Ryan, A. and Cummins, J. Microbial Ecology in Health and Disease (in press).

10. Jakowitsch, J., et al. Proc. Nat. Acad. Sci. USA 96, 13241-13246 (1999).

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