For our third day of laboratory work experience, the day started at 9 o’clock (again) with an inspection of the previous day’s work, i.e. looking at the “streak” plates of all the bacterial cultures that the group had made. It was fair to say we had mixed success, with some microorganisms like E.coli growing like weeds and providing a good full plate and some other types and strains of bacteria appearing to be dead or at least taking more time grow. So for those bacteria that hadn’t grown much, it was back into the incubator at 37ºC to be given a further chance to grow.
After this, we set about working in smaller groups, with one group producing streak plates on M17 agar, whilst another made an initial spreadsheet in order to catalog the microorganisms that we’d worked with. Finally, the last group set about making M17 broth, M17 agar and TYG agar. After these tasks were done, at around 10:30am, we had a break before we were to learn all about the world of blogging from Joss Winn who is a senior lecturer in the Centre for Excellence in Research and Development (CERD), which is based at the University of Lincoln in the MHT building, and headed by Professor Mike Neary the Pro-Vice Chancellor for teaching and learning.
At 12:30pm, we met Joss who provided with some training in the use of WORDPRESS “blogging” software and also showed us how to build the website that we would use to create and publish this very blog on. Turns out that there is a lot more to blogging than meets the eye!
Afterwards, we attended a lecture given Dr Andrew Westwell, a scientific collaborator of Dr. Tim Bates (who organised the lab. work experience described in this blog). Dr. Westwell is a Senior Lecturer in Medicinal Chemistry in the Welsh School of Pharmacy at the University of Cardiff. He was describing experiments using a new drug that had been synthesised by his team called ‘Phortress’ which is designed to act against breast cancer associated with an enzyme called E3 ubiquitin ligase (BCA2). His work is so much more complex than the undergraduate lectures on breast cancer, which meant that we were left feeling somewhat confused by the highly technical terms. But it must be said that Dr. Westwell and his peers have created a very important compound which is currently undergoing the first stage of clinical trials, in association with Cancer Research U.K.. Below is a summary of the lecture giving more detials on the developing novel drug:
What makes a good cancer drug? Efficacy, specificity, ease of formulation and delivery as well as having a high bioavailability. During the development of a new novel anticancer drug these criteria must all be met. The steps that Dr Westwell and his team had to take to produce their most effective drug to date included the development of a group of 2-4(aminophenyl)benzothiazole compounds and consideration of the metabolic changes that would occur to the drug in vivo in man, for example, hydroxylation which can change the properties of the drug. After manipulation which included adding fluorine to the molecule to prevent these changes – PHORTRESS was synthesised. This then went into investigation at the Cancer Research UK labs in Newcastle and London where the first pass metabolism (in the liver) came to their attention. The researchers there avoided this problem by developing a range of amide "prodrugs" which enabled the drug to be water soluble and administered by injection.
PHORTRESS has a novel structure and mechanism with a high potency and specificity. It involves only one step conversion so there is ease of manufacture. Fluorescence and other techniques such as Positron emisssion tomography can used as imaging modalities to see where the drug is deposited in the body, as the molecule includes fluorine which makes the molecule fluorescent, and fluorine can also be used ot make positron emitting version of the PHORTRESS molecules..
The Ubiiquitin-protease system is targeted using this molecule, as there is a selective net uptake of the chemical which ultimately leads to cell damage and death via inhibition of the ubiquiting-proteosomal pathway.
BCA2 is only expressed in cancerous tissues, it can be isolated in the cytoplasm and nucleus, this is correlated with positive oestrogen recetor status and allows another target of the drug. This molecule has a significant ring domain structure involving cytene and histamine structure, this unique shape along with computer modelling can help scientists like those at the Cardiff university and at the Cancer Research Facility in Nottingham to adapt and engineer molecules with specificity with the BCA2 structure.
The Rab-7 molecule is very important in trafficking and decreases expression of the BCA2 which in turn reduces Rab-7 and consequently an increase in EGF-R(Growth factor degredaton). This means that the Rab-7 molecule has a negative effect on the growth of the tissue and therefore prevents proliferation of the tissue.
Dr Westwell mentioned the importance of disulphide bonds, these have a high affinity for zinc and inhibit expression of BCA2 which leads to growth inhibition. As this effect is only apparent with cells expressing the BCA2 gene, normal cells are not affected.
Although this drug has opened up a new point of entry into the battle against cancer, as scientists we must assess the overall effects of this molecule and continue research to determine the actual mprecise molecular mechanisms of thi and other anti-cancer molecules, as is happening in the laboratory of Dr. Bates, at the University of Lincoln).
Following this research lecture, which left many of us in a slight “daze”, we retreated back to the microbiology research laboratory, in order to sort out who would be working on what task for the following morning:
So to finish this blog, dear reader, here is a joke loved by scientists the world over:
An electron and a proton went into a bar. The proton says to the electron, “your round”, the electron replies “you sure?”, so the proton says “I’m positive”.
Oh dear…
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