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Reply to “Use of genetically modified microbes for human health”

Prof. Joe Cummins, Department of Biology, Ontario, Canada & Dr. Mae-Wan Ho Biophysics Group, King’s College, London, UK

Gregor Reid et al (1) commented on our article, “Genetically modified probiotics should be banned” (2), and promoted the use of genetically modified microbes for human health, which we shall address.

We take issue first with the closing salvo of Reid et al (1), which took the isolated words, ‘rogue’, ‘nasty’, and ‘warfare’, in our article out of context as representing sensationalism and a lack of common sense.

We used “warfare” in referring to and quoting from a review (3): “An earlier review discussed bacterial replacement therapy as a form of ‘germ warfare’ to prevent and control infections of skin, oral cavity, ears and uro-genital tract”. The analogy of germ warfare is commonplace; as for example the web page for Canadian Research and Development Centre for Probiotics headed by Gregor Reid features the article “Microorganism Warfare” (4).

The term “rogue” appeared as follows: “The vast majority of applications have been free of pathological outcomes; but there has been one case of local infection from a rogue Lactobacillus strain. “ “Rogue” in the literature of genetics and microbiology refers to an aberrant individual or colony. A quick scan of the PubMed search turned up over 5000 articles using the term in the medical literature.

The term “nasty” appeared in the following context: “experience tells us that interfering with the immune system can lead to nasty surprises, as in the case of the harmless mousepox virus that turned into a lethal pathogen when a gene that was supposed to boost antibody production was inserted into it.” The PubMed search revealed 87 uses of the term “nasty” in medical journals including The Lancet, Nature Medicine and many other journals.

Reid et al (1) objected to our definition of probiotics (2) as “naturally occurring bacterial strains belonging to species found in the human gut, and are being added to food for their health-promoting effects.” Instead, they fall back on the definition (5, 6): “Live microorganisms which when administered in adequate amounts confer a health benefit on the host.” The main difference is to omit the word “natural”, presumably to insure that genetically modified bacteria may be described as probiotic. That is misleading and dangerous, as argued in our paper (2) and below, given the long tradition in the safe use of probiotics before genetically modified bacteria were considered.

Reid et al (1) cited as an example of appropriate probiotic therapy, a phase I trial of Lactococcus lactis modified with a synthetic approximation of the human interleukin 10 gene for treating Crohn’s disease. The synthetic interleukin 10 gene was linked to a gene for making the bacterium dependent on thymidine for growth (7, 8). The experiment was deemed successful even though there was little or no effort to search for bacteria that contained the synthetic human interleukin gene, but were no longer thymidine-dependent as the result of genetic recombination or horizontal gene transfer, or both. Such bacteria will continue to synthesize interleukin 10 whether it is needed or not, disturbing the intricate network of immunological adaptations between natural gut bacteria and human host (2) with potentially deleterious health impacts.

Reid et al (1) stated: “Bacterial genetic alterations occur all the time in nature, often precipitated by the action of humans, as exemplified by over-use of antibiotics.” There is ongoing debate as to whether the bacterial genetic alterations were ‘adaptive’ or ‘directed’ mutations (9), but no evidence that antibiotics are directly mutagenic.

Past experience tells us that horizontal gene transfer and recombination is an important, if not the most important route to creating new pathogens, and that will be readily accomplished by genetically modified probiotic bacteria (2). Bacteria modified  with synthetic approximations of  human genes cannot be deemed substantially equivalent to the antibiotic resistant bacteria arising in nature.

We take issue most of all with the assertion of Reid et al (1) that microbial gene therapy for HIV is ‘probiotic’. This is highly misleading in view of the hazards we have pointed out in our paper (2) and reiterated above.

Microbial gene therapy should be recognized as a practice separate and distinct from probiotics, and risk assessed accordingly.

Article first published 03/07/06


References

  1. Reid G, Gibson G, Gill H, Klaenhammer T, Rastall R, Rowland I and Sanders M. Use of genetically modified microbes for human health, letter to the editor.
  2. Cummins J and Ho MW.  Genetically modified probiotics should be banned.  Microbial Ecology and Health and Disease  2005;17: 66-8.
  3. Tagg J, Dierksen K. Bacterial replacement therapy: adapting germ warfare to infection prevention. Trends in Biotechnol.2003; 21: 217-23.
  4. McTighe D. Microorganism warfare  Canadian  Research and Development Centre for Probiotics  2006 http://www.crdc-probiotics.ca/
  5. FAO/WHO. Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations and World Health Organization Expert Consultation Report. 2001.
  6. Rastall RA, Gibson GR, Gill HS, Guarner F, Klaenhammer TR, Pot B, Reid G, Rowland IR, Sanders ME. Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications. FEMS Microbiol Ecol. 2005; 52(2): 145-52.
  7. Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L  A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn’s Disease. Clin Gastroenterol Hepatol. 2006; May 19 [Epub ahead of print]
  8. Steidler L, Neirynck S, Huyghebaert N, Snoeck V, Vermeire A, Goddeeris B, Cox E, Remon JP and  Remaut E. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol. 2003; 21:785-9.
  9. Rosenberg SM and Hastings PJ. Modulating mutations rates in the wild. Science 2003; 300: 1382-3.

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