| Resumo: |
The SYNBIOBACTHER project aims to use synthetic biology strategies to design "therapeutic" bacteria, specifically to be used in treatment of solid tumours. Statistics show that over 1.2 million persons will be diagnosed with breast cancer worldwide this year, hence this is an enormously important health risk, and progress leading to enhanced survival is a global priority. Several strategies have been pursued over the years, whether searching new biomarkers, drugs or treatments [26-27]. Ultrasound is one of the techniques often used to treat solid tumours; however, this technique is not always successful, as sometimes it just heats the tumour without destroying it. If it would be possible to link this treatment with the expression/release of a therapeutic agent, the joint effect could be more effective. Some efforts have been made in this direction, although to date the results have not been very encouraging; potential reasons include lack of precise control over administration of the drug. Therefore, our idea is to overcome this barrier through the use of synthetic biology strategies to engineer a model bacterium to trigger release of a therapeutic agent concurrent with ultrasound treatment. The search for new cancer-fighting drugs has traditionally driven research efforts in this field. Curcumin, due to its attractive properties as a novel drug has recently attracted increased attention. Nevertheless, it is well known that it has a poor bioavailability. Cellular uptake is slow, and it is quickly metabolised once inside cells, requiring repetitive oral doses to achieve sufficient concentration inside the cells for therapeutic activity [14]. Hence, the possibility of synthesizing curcumin in situ in a controlled way, as proposed in this project, provides a powerful alternative. Synthetic biology seeks to reprogram cells to perform new tasks under specific control by using several modular genetic parts comprised of cell-based environmental sensors and g  |
Resumo
The SYNBIOBACTHER project aims to use synthetic biology strategies to design "therapeutic" bacteria, specifically to be used in treatment of solid tumours. Statistics show that over 1.2 million persons will be diagnosed with breast cancer worldwide this year, hence this is an enormously important health risk, and progress leading to enhanced survival is a global priority. Several strategies have been pursued over the years, whether searching new biomarkers, drugs or treatments [26-27]. Ultrasound is one of the techniques often used to treat solid tumours; however, this technique is not always successful, as sometimes it just heats the tumour without destroying it. If it would be possible to link this treatment with the expression/release of a therapeutic agent, the joint effect could be more effective. Some efforts have been made in this direction, although to date the results have not been very encouraging; potential reasons include lack of precise control over administration of the drug. Therefore, our idea is to overcome this barrier through the use of synthetic biology strategies to engineer a model bacterium to trigger release of a therapeutic agent concurrent with ultrasound treatment. The search for new cancer-fighting drugs has traditionally driven research efforts in this field. Curcumin, due to its attractive properties as a novel drug has recently attracted increased attention. Nevertheless, it is well known that it has a poor bioavailability. Cellular uptake is slow, and it is quickly metabolised once inside cells, requiring repetitive oral doses to achieve sufficient concentration inside the cells for therapeutic activity [14]. Hence, the possibility of synthesizing curcumin in situ in a controlled way, as proposed in this project, provides a powerful alternative. Synthetic biology seeks to reprogram cells to perform new tasks under specific control by using several modular genetic parts comprised of cell-based environmental sensors and genetic circuits [3,5,12]. Promising applications in the medical arena include the design of bacteria to produce therapeutic agents (in vitro or in vivo) and the use of live bacteria as targeted delivery systems [1-2,7]. Therefore, the proposed tasks involve several different modelling and engineering steps to program E. coli to execute a new synthetic pathway for curcumin production triggered by a temperature increase. The heat shock response machinery of E. coli will be used as a sensor in the design of the "therapeutic" bacteria, due to the fact that the synthesis of heat shock proteins is rapidly and selectively induced when temperature is raised [14-15]. Regarding the curcumin pathway, databases and the literature will be screened in order to obtain the gene sequences of the enzymes involved, and afterwards these will be synthesized and introduced in the E. coli genome according to several cloning strategies. Several validation steps will insure that the occurrence of (unwanted) side-product formation and/or accumulation is minimized. Moreover, the induction system will also be tested and optimization tasks are foreseen to improve the production of curcumin by E. coli. It is important to notice that the main goal of this project is to achieve the proof-of-concept that the engineered system will enable the production of curcumin triggered by a temperature increase. Results from this project will naturally raise several other questions that might be addressed in further research, such as the insertion of the pathway in the chromosome, safety and ethical issues, and experimentation in cancer models. |