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Applications to the MRC Toxicology Unit PhD programme

Applications are now open for PhDs to start in Lent term (January 2023). If you are interested in applying, please follow these guidelines. First, prior to submitting your application, you must ensure that you meet all of the University of Cambridge entry requirements.

Important deadlines

Official start date Deadline
January 2023 (Lent)  4th October 2022

Submission of applications

Funded PhD projects, commencing in January 2023 (Lent term):

These PhD projects are for four years and come with funding for tuition fees (at Home rate) and a maintenance stipend of £17,500 per annum.

Applicants must secure the support of a supervisor within a laboratory before their application will be considered.

To be eligible for full funding candidates will need to demonstrate that they have Home fee status. See here for more detailed information.

Candidates of any nationality/residency can also apply and will be considered for a fees-only (at Home rate) award.  Candidates would therefore need to secure additional funds from other sources to cover the higher tuition fee and their maintenance stipend. The most current estimates of costs can be found on the Graduate Admissions fees page.

Application process:

  1. Read and research the description of the funded projects below.
  2. Download and complete our informal application form (here), paying attention to the guidelines in red.
  3. Email the completed form to the potential supervisor(s), stating your intention to apply for a PhD
  4. The potential supervisor will review your email and, if appropriate, they will contact you for an informal discussion.
  5. Following the initial discussion, the potential supervisor(s) will advise you whether to make a formal application through the Applicant Portal, here. The course is listed in the Application Portal as "Biological Science (MRC Toxicology Unit) PhD".The closing date for formal applications is 4th October 2022 and it is recommended that you take time to check the application requirements including the documentation you will need to upload here.
  6. The department will review your aplication and you will be invited to attend interview if shortlisted.
  7. If your application is successful, a conditional offer is communicated by email and the self-service account.

Description of funded projects

Project M22-11

Exploring the Molecular Mechanism of Novel Mitochondrial Neurotoxins identified through a Machine Learning Approach

Supervisors: Dr. L. Miguel Martins (MRC Toxicology Unit) and Dr. Emmanouil Metzakopian (Bit.bio)

Mitochondrial inhibition is an important ‘OFF-target’ mechanism of drug-induced toxicity in the clinic, contributing to drug attrition in clinical trials and drug withdrawal following approval because of severe adverse events 1. We have recently developed metabolic shift assays to screen antipsychotic drugs for off-target mitochondrial toxicity (Hardy, manuscript in preparation).

In this project, we will use machine learning algorithms 2,3 to discover mitochondrial liabilities, inherent in neuroactive compounds. The student will then focus on characterising these drugs - representing different structural classes - for evaluating mitotoxicity in cultured human neurons. We will train a neural network on a curated list of chemical inhibitors (~200 compounds) of mitochondrial respiratory complexes. The trained neural network will be then used to identify novel mitochondrial toxins in drug libraries such as the Prestwick chemical library. Using a suite of cellular and cell-free biochemical assays, we will then explore the molecular mechanisms underlying the mitochondrial toxicity. For selected targets, we will use thermal proteome profiling 4,5 to identify mitochondrial drug targets followed by in silico docking to define chemical binding properties. As mitochondrial toxicity is involved in Parkinson’s disease and Frontotemporal dementia, we will screen for adverse effect of these drugs in human neurons and glial cells, as co-culture and/or organoids derived from induced pluripotent stem cells (iPSCs). The collaboration with bit.bio will offer access to a range of mature CNS cell types derived with consistent quality from wild-type or disease mutation-bearing isogenic iPSC lines by applying controlled cellular reprogramming (opti-ox™). On another hand, while there is emerging evidence on the impact of mtDNA variants on human iPSC biology and applications 6, the project will further include the exploration of heteroplasmy and its consequences on hiPSC differentiation and their use as neurotoxic models. This part of the project will be run in close collaboration with the bit.bio research team and could include the development of QC assays and mitochondria targeted interventions towards the improvement of iPSC based in vitro models.

The project will provide the student with training in a wide range of innovative wet lab approaches, exposure to both academic and industry work environments, and importantly an opportunity to integrate experimental laboratory skills with ‘in silico’-based approaches.

1          Dykens, J. A. & Will, Y. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today 12, 777-785, doi:10.1016/j.drudis.2007.07.013 (2007).

2          Allen, T. E. H. et al. Neural network activation similarity: a new measure to assist decision making in chemical toxicology. Chem Sci 11, 7335-7348, doi:10.1039/d0sc01637c (2020).

3          Periwal, V. et al. Bioactivity assessment of natural compounds using machine learning models based on drug target similarity. bioRxiv, 2020.2011.2006.371112, doi:10.1101/2020.11.06.371112 (2021).

4          Savitski, M. M. et al. Tracking cancer drugs in living cells by thermal profiling of the proteome. Science 346, 1255784, doi:10.1126/science.1255784 (2014).

5          Perrin, J. et al. Identifying drug targets in tissues and whole blood with thermal-shift profiling. Nat Biotechnol38, 303-308, doi:10.1038/s41587-019-0388-4 (2020).

6          Palombo, F. et al. The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs. Stem Cell Reports 16, 1953-1967, doi:10.1016/j.stemcr.2021.06.016 (2021).

 

Self-Funded PhD students only:

These projects do not have funding attached. You will need to have your own means of paying fees and living costs and / or seek separate funding from student finance, charities or trusts.

  1. Begin by checking that the supervisor you want to approach is accepting research students by seaching his / her name in the Research Teams database of the Post Graduate School of Life Sciences, here.
  2. Download and complete our informal application form (here), paying attention to the guidelines in red.
  3. Email the completed form to the potential supervisor, stating your intention to apply for a PhD.
  4. The potential supervisor will review your email, they may also contact you for an informal discussion.
  5. Following the initial discussion, the potential supervisor will advise you whether to make a formal application through the Applicant Portal, here. The course is listed in the Application Portal as "Biological Science (MRC Toxicology Unit) PhD". The closing date for self-funded applications is 16th May 2022 and it is recommended that you take time to check the application requirements including the documentation you will need to upload here.
  6. The department will review your aplication and you will be invited to attend interview if shortlisted.
  7. If your application is successful, a conditional offer is communicated by email and the self-service account.