Advancing diagnostics for precision medicine in severe infection

Commercial partner: Danaher

This project aims to advance precision medicine for severe infections by identifying informative biomarkers that may indicate when the normally protective immune response to infection becomes maladaptive, leading to life-threatening organ dysfunction and the clinical syndrome of sepsis.

The academic supervisors Knight and Mentzer have established deeply phenotyped longitudinal cohorts of patients with severe infection and identified patient subgroups (or endotypes) using white blood cell transcriptomics and plasma proteomics that are informative for immune state, outcome and drug response (refs 1-5). Specifically, they have identified an endotype with features of immunosuppression and bone marrow dysfunction that may be targetable for personalized therapy.

An academic-industry partnership has been established through a Danaher Beacon (https://www.ndm.ox.ac.uk/news/partnership-with-danaher-to-pave-the-way-for-precision-medicine-tests-for-sepsis) to develop a point-of-care diagnostic (POCD) for this immunosuppressed endotype. This will use a multiplex reverse-transcriptase PCR assay for a specific sepsis response signature (SRS) of blood transcribed genes originally identified by the Oxford team.

The proposed project will build on these findings and resources to investigate

(1) clinical use cases for the SRS POCD including implementation in predicting patient trajectories in patients presenting to the emergency department, or acutely deteriorating with hospital-acquired infections, and subsequent actioning on these results

(2) how combinations of other biomarkers (for example clinical, transcriptomic, proteomic, immunological) in sepsis patients, or those at risk of developing sepsis, may be informative for interrogating the response to infection and informing clinical decision-making

(3) identifying pharmacological interventions that could be tested in the sepsis endotypes following POCT identification, laying the foundation for potential future clinical trials

Prospective data collection will be complemented by large in-house datasets available for data mining such as the UK Genomic Advances in Sepsis (GAinS) study. The project will involve big data approaches including artificial intelligence, developing innovative ways to combine molecular phenotyping with data from the electronic health care record and physiological monitoring, and how this can be most effectively translated to patient care.

For the student, the project will provide an outstanding opportunity to gain training in and advance precision medicine, diagnostic and data analytics, aligning with the MRC’s remit and Strategic Delivery Plan. This includes advanced data science methods for data analytics and machine learning using complex high dimensional datasets spanning human health and biology.

The project is highly collaborative, building on strong existing relationships between the proposed supervisors in academia and industry settings, and will help promote innovation and researcher mobility between sectors. The supervisors Knight, Mentzer and Tsalik are clinician scientists with established expertise and track records of research outputs in this field, and Tsalik brings significant industry expertise. The project will accelerate development and application of a POCD for patient benefit, advance understanding of pathophysiology, and provide a paradigm for precision medicine in this field.

1. Mi, et al. Science Translational Medicine 16, eadh0185 (2024).

2. Kwok et al. Nat Immunol 24, 767-779 (2023).

3. Cano-Gamez. Sci Transl Med 14, eabq4433 (2022).

4. Davenport et al. Lancet Respir Med 4, 259-71 (2016).

5. Antcliffe et al. Am J Respir Crit Care Med 199, 980-986 (2019).

Apply using course: DPhil in Clinical Medicine

MRC INDUSTRIAL CASE STUDENTSHIPS 2025

Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.

ELIGIBILITY

They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.

FUNDING PACKAGE

Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.

APPLICATIONS DEADLINE

Applications must be received by 12 noon (UK time) Tuesday 3 December 2024. Details on entry requirements and how to apply can be found below.

For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.

HOW TO APPLY

Before applying for this project we recommend you contact the lead supervisors for informal discussion.

To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.

If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.

If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email [email protected].