University College London Featured PhD Programmes
Engineering and Physical Sciences Research Council Featured PhD Programmes
University College London Featured PhD Programmes
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University College London Featured PhD Programmes

A 3Rs approach to assess drug toxicity on the embryo during early pregnancy in vitro


Project Description

This project offers an exciting opportunity for a motivated student to contribute to new understanding on the effects and safety of drugs taken during pregnancy on the developing embryo. Pregnant women, or women trying to conceive, need to be aware of the risks posed by any medication they may have to take during pregnancy, especially important during the 1st trimester. The general advice given to women is not to take medication at all during their pregnancy, and medication is only usually prescribed when the benefit to the mother outweighs the potential effects on the embryo. We therefore require adequate information on the effect of current and new drugs during pregnancy, especially when treating conditions where withholding treatment might not be prudent.

Developmental and Reproductive Toxicity studies (DARTs) in animals are required to assess the effect of drugs during pregnancy, however they are highly expensive, use large numbers of animals, and it is unknown how well they predict human developmental toxicity. Furthermore, the absence of any effect in animal tests does not necessarily mean a drug is safe to take during pregnancy. Although there are validated in vitro alternatives, none of these provide an integrated approach to look at the early developing embryo.
We have developed a novel 3D tissue-culture protocol that uses small numbers of mouse embryonic stem cells (mESCs), grown in suspension. Over time, these “gastruloids” mimic many of the early developmental events seen during mouse development: symmetry-breaking, polarised gene expression, axis elongation and formation of 3 embryonic axes1-3. Gastruloids are highly tractable, allowing precise experimental manipulation, which is difficult to do with embryos. It is for these reasons that we believe that gastruloids may be able to substitute mice during DARTs.

This project will allow us to gain insight into drug-induced developmental toxicity in a model that can be tailored to human development, providing us with an experimental platform that has the potential to greatly reduce the use of animals in DARTs. This will be accomplished through the following objectives:

Objective 1: Test whether known teratogenic drugs and their metabolites e.g. Thalidomide (THD) or valproic acid (VPA) can disrupt axial patterning in the gastruloids in a way that mirrors their effect in vivo (collaborating with Prof. Neil Vargesson, Aberdeen). Generate reporter cell lines will be established to report on the development of multiple axial markers in real time, monitoring normal & drug-induced alterations in patterning.

Objective 2: Couple gastruloids to an in vitro flow model of a zonated liver4 to generate metabolites of parent compounds and assess the effect of these on gastruloid patterning and progression in real time (collaborating with Dr. P. Sharma; Dept. Pharmacology), specifically focusing on anti-epileptic drugs.

Objective 3: Establish a method for generating gastruloids from human ESCs and iPSCs (collaborating with Prof. A Martinez Arias, Cambridge). Test whether human gastruloids can recapitulate patterning defects from known teratogens and predict the effect of drugs with unknown reproductive/developmental toxicity.

Training: The IACD is an excellent multidisciplinary research environment with direct links to unique technological platforms and technical expertise, ideal for the student to learn valuable laboratory techniques and skills for their future career. The supervisors will train the student in all aspects of the project, including techniques such as PCR, advanced microscopy, molecular biology, and stem cell culture. Valuable experience will be gained from working within a multidisciplinary environment with regular access to journal clubs, research seminars and group meetings. IACD also runs workshops for students on Experimental Design and Statistical Analysis. Broader research training will be provided through the university’s PGR training programme and doctoral training college. IACD has a strong record in public and patient engagement, and has won awards for past events. Training is available and the student will be strongly encouraged to get involved in and lead such events.

This project is most suitable to a student with an undergraduate or Master’s degree in Developmental Biology, Pharmacology, or a related Life Sciences subject (Biology, Genetics, Biochemistry, Biomedical Sciences, Cell Biology, and Medicine).

Enquiries to: Dr David Turner ()

To apply: please send your CV and a covering letter to Dr. David Turner () with a copy to

Expected interview date/week:
Closing date for applications: 13th January 2020
Expected week for interviews: w/b 10th February 2020

Studentship commences 1st October 2020.

Funding Notes

This PhD studentship is fully funded by the NC3Rs (View Website), consisting of an annual maintenance grant starting at ~£15,000 in year 1; bench fees are also covered by the studentship. The successful candidate should have, or expect to have, an Honours Degree at 2.1 or above. Candidates whose first language is not English should have an IELTS score of 6.5 or equivalent.

References

1. van den Brink, S. C. et al. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development 141, 4231–4242 (2014).
2. Turner, D. A. et al. Anteroposterior polarity and elongation in the absence of extraembryonic tissues and spatially localised signalling in Gastruloids, mammalian embryonic organoids. Development 144, dev.150391–3906 (2017).
3. Beccari, L. et al. Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids. Nature 562, 272–276 (2018).
4. Tomlinson, L. et al. In vitro Liver Zonation of Primary Rat Hepatocytes. Front. Bioeng. Biotechnol. 7, 253–8 (2019).

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