Sir,
The publication by Ott et al. Citation[1] restates the important, and topical, use of microbes in treating disease, in this case lymphoid immunodeficiencies. However, not everyone agrees that recombinant bacteria should be used in humans, and one particular submission to this journal called for a ban of such uses, a viewpoint that we wish to now strongly challenge Citation[2].
The primary concerns, quite rightly, are safety and avoidance of overt environmental release. However, we believe that there are very good reasons for continuing to develop novel recombinant probiotic technologies. In a precedent-setting case, the insertion upstream and downstream of thyA flanking a series of hIL10 expression cassettes in Lactococcus lactis LL-Th12 Citation[3] was sufficient for the Dutch regulatory agency to permit human trials with this organism. The results showed expression of human interleukin 10 (IL-10) and no detectable environmental release of the organism occurred. This was due to the requirement for thymidine or thymine for growth and survival Citation[4].
Bacterial genetic alterations occur all the time in nature, often precipitated by the action of humans, as exemplified by overuse of antibiotics. Genomic sequencing has shown that Lactobacillus species hold no major virulence properties, and this is leading to the creation of recombinant strains that may potentially prevent HIV, enhance host cell deficiencies, treat inflammatory disease, and provide oral vaccination routes for the prevention of viral and bacterial pathogens Citation[5–7].
Collectively, scientists and regulators must explore ways to balance safety and environmental exposure with the benefits that recombinant organisms might provide. Whether the end target is immunodeficiencies or other diseases, particularly those causing enormous suffering and death around the world, the use of recombinant lactobacilli or avirulent 'pathogens' should be permitted if sufficiently stringent preclinical testing has been performed and adequate surveillance systems are in place. Such rational steps, and reasoned arguments, differ markedly from the approach taken by Cummins and Ho Citation[2], whose use of words such as 'rogue', 'nasty', and 'warfare', and an unknown definition of probiotics - instead of a generally agreed upon definition Citation[8], Citation[9] - appear to focus more on sensationalism than on common sense.
References
- Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006; 12: 401–9
- Cummins J, Ho M-W. Genetically modified probiotics should be banned. Microb Ecol Health Dis 2005; 17: 66–8
- Steidler L, Neirynck S, Huyghebaert N, Snoeck V, Vermeire A, Goddeeris B, et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 2003; 21: 785–9
- Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L. A phase I trail with transgenic bacteria expressing interlewkin-10 in Crohn's disease. Clin Gastroenterol Hepatol Jun 2006; 4(6)754–9
- Steidler L. Yakult International Symposium, Ghent, Belgium, 13 October, 2005.
- Pusch O, Boden D, Hannify S, Lee F, Tucker LD, Boyd MR, et al. Bioengineering lactic acid bacteria to secrete the HIV-1 virucide cyanovirin. J Acquir Immune Defic Syndr 2005; 40: 512–20
- Liu JJ, Reid G, Jiang Y, Turner MS, Tsai CC. Activity of HIV entry and fusion inhibitors expressed by the human vaginal colonizing probiotic Lactobacillus reuteri RC-14. Cell Microbiol. 2006 Jul 31; [Epub ahead of print].
- Chang TL, Chang CH, Simpson DA, Xu Q, Martin PK, Lagenaur LA, et al. Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4. Proc Natl Acad Sci U S A 2003; 100: 11672–7
- 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. http://www.fao.org/es/ESN/Probio/probio.htm.
- Rastall RA, Gibson GR, Gill HS, Guarner F, Klaenhammer TR, Pot B, et al. 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: 145–52