Ph.d-forsvar Karen Martinez-Swatson – Københavns Universitet

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Ph.d-forsvar Karen Martinez-Swatson

Domesticating deadly carrots. Insights into the biosynthesis of thapsigargin within the genus Thapsia L.

The demand of thapsigargin both in drug development (Mipsagargin, a prodrug for the treatment of solid tumours) and as a tool to investigate cell apoptosis has been very high and is set to increase substantially. However, the compound is only available through the extraction of fruits from wild populations on Ibiza of Thapsia garganica, a species which belongs to the poorly defined genus Thapsia L. There is, therefore, a pressing need to discover thapsigargin's biosynthetic pathway and to develop alternative production platforms. In this PhD project, over 230 samples were collected from across the Mediterranean and herbaria and used to expand our phylogenetic understanding of circumscription of the genus and its species. Chemical variation of Thapsia was investigated across its native range. Seeking to find the primary trigger for this chemical variation in a greenhouse experiment, it was shown how inducing tissue damage to leaves (to mimic herbivory), was shortly followed by the activation of the species’ chemical defence. Mass spectral molecular networking further enabled identification of so far unknown molecules closely related to thapsigargin that would be worth investigating further to discover new drug leads or intermediates in the thapsigargin biosynthetic pathway. The effect of the environment on the species’ chemistry was further investigated by sampling wild populations of Thapsia garganica in Ibiza, to see whether herbivory and other abiotic or biotic factors in the species natural environment were responsible for the variations observed between its different chemotypes. Here it was found that locality played a significant role in the chemical variation of the species, and that this changed during the growth period of individual plants. A collaboration with an Algerian partner further demonstrated the effect of locality on the levels of thapsigargins in the species as well as providing an opportunity to test out different chemical extraction methods to improve the chemical analytical methods. To identify the site of biosynthesis of thapsigargin, a histochemical analysis coupled with MALDI imaging showed that the specialised structures in the roots play an important part in producing and storing the highly toxic compounds the species uses to defend itself against herbivory. Herbarium material, both existing and new additions to the collection after sampling, illustrate the importance of collections not only in preserving knowledge and being key to identifying plant species but also in plant drug discovery research.

Supervisors

  • Professor Nina Rønsted (Natural History Museum, Denmark).
  • Associate Professor Henrik Toft Simonsen (Technical University of Denmark)

 

Assessment Committee

  • Professor Tom Gilbert (Head of section for EvoGenomics, Natural History Museum, Denmark) – chairman
  • Professor Pinarosa Avato, Department of Pharmacy, University of Bari, Italy.
  • Professor Krzysztof Spalik, Department of Molecular Phylogenetics and evolution, University of Warsaw, Poland.