1. Lecture 8 The Genetic Manipulation of NPs

2. Learning Outcomes Genetic manipulation of NP metabolism Why one might want to manipulate NPs composition? What could occur if you try to manipulate NP pathways? The concept of Equivalence – does it help? The value of Metabolomics – will it help The good, the bad and the ugly

3.  increase yield of endogenous NP  change relative % of NPs  produce new, higher value, products by introducing an exotic NP  reduce costs, maybe by processing  reduce losses due to:  insects … some NPs might help?  fungi … some NPs might help?  weeds … some NPs might help?  viruses … some NPs might help?  bacteria … some NPs might help? Why might you want to alter NP composition?

4. Genetic manipulation of NP Metabolism – we get into the old arguments that have hindered the adoption of GM crops in Europe and cause concern elsewhere There can be no hard and fast rules – “GM is safe” or “GM is dangerous” are both gross oversimplifications. Safe for which organism? Safe under which conditions? We can never prove anything is safe, we can only give a statistical evaluation of risk.

5. Genetic manipulation of NP Metabolism – are NPs different? The addition of a gene to an organism simply adds the capacity to make a new protein – it is the properties of the protein that matter. Proteins possess different properties. Addition of a gene coding for a new protein, which is simply a toxin, like the Bt toxin, will change the plant in a fairly predictable way. The plant will be identical except for containing Bt protein? Note that the addition of the Bt gene could have predictable and unpredictable ecological consequences.

6. Old paradigmNew paradigm

7. Genetic manipulation of NP Metabolism. Genetic manipulation of NP Metabolism – are NPs different? The SH model suggests that the introduction of a gene coding for a protein that is an enzyme involved in NP metabolism will produce an uncertain outcome. It is possible that more than one new product will be made by the plant or microbe (due to its broad substrate tolerance). Furthermore, the existing NP metabolism enzymes in the pathway may make yet more chemical diversity What about the consequences of introducing an enzyme?

9. Old paradigmNew paradigm

11. Phenylpropanoid pathway

12. Genetic manipulation of NP Metabolism. Not everyone accepts this analysis T M Kutchan (2005) Trends in Biotech. 23, 381 “ … how are metabolic pathways affected upon introduction of a transgene? … plants can be tailored in a rational manner with marginal inadvertent effects.” “ … This is an exciting milestone along the way to general public acceptance of genetically modified plants” But others are exploiting exactly the flexibility that the SH predicts Polyketide pathway

13. Genetic manipulation of NP Metabolism - polyketides.

15. Genetic manipulation of NP Metabolism - Polyketides

16. Genetic manipulation of NP Metabolism - Polyketides.

17. Genetic manipulation of NP Metabolism -polyketides.

19. Genetic manipulation of NP Metabolism. “Equivalence” and Testing– enough to avoid problems? Equivalence – bread flour in normal and Bt wheat fairly easy to judge Equivalence – is a spearmint plant equivalent to a peppermint?

20. Analytical Testing – “metabolomics” look for which chemicals? at what sensitivity? under what growing conditions? after which challenges? do we know enough about the toxicological properties of the many NPs found

21. Genetic manipulation of NP Metabolism Summary  NP metabolism has evolved to be flexible and unpredictable.  The manipulation of NP metabolism will be possible but the outcomes will inevitably be unpredictable.  Because NP are involved in organism interactions, and because such interactions are poorly understood, caution might be wise.  But the good news is that most unplanned, weird new NPs that arise through GM will have a low probability of possessing biomolecular activity.