Bioanalysis Rising Star Award finalist: Danielle Moncrieffe

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Nominated by: David Cowan (King’s College London, UK)

Supporting comments:

“Her work on P-III-NP has been recognized as it has progressed, first within the department (2017), then nationally (British Mass Spectrometry Society’s best student presentation, Barber prize, 2017), and internationally (MDI award, Cologne, 2018 and the Partnership for Clean Competition award, 2019).

Danielle showed her ability to handle the complex nanospray LC–MS technology with a variety of model compounds including, IGF-I and insulins at 7 pg/ml. Our national anti-doping organization used her results to move from collecting urine samples to blood for detecting insulin misuse. This initial work enabled her to handle P-III-NP where we had just a poorly authenticated sample of bovine material. She mastered the UniProt system where currently the molecule is not fully characterized, especially with respect to its many post-translational modifications. She was undaunted throughout her 4-year PhD research being able repeatedly to return to a firm footing before venturing into the unknown.

She is continuing her work to help advance the field of bioanalysis in the area of developing novel approaches to be able to quantify large peptides in biological fluids at small concentrations. Of special relevance is being able to obtain identical results with whole blood, serum or plasma; this being a very challenging undertaking.”

 1Describe the main highlights of your bioanalytical work.

I am the first to develop a LC–MS method to identify procollagen III amino-terminal propeptide (P-III-NP, a clinical biomarker of liver disease and growth hormone administration), undertaken in the absence of human reference material. Using genomic databases and a sample of bovine P-III-NP (sharing 97 % sequence homology with human) elucidation of post-translational modifications enabled the design of appropriate target peptides (intact P-III-NP being too large to measure with current technologies) to develop a LC–MS measurement approach. Using these uniquely designed peptides, sensitive LC–MS methodologies were developed on a Waters Xevo TQ-S using nano- and micro- LC–MS setups to achieve LOD’s of 5 and 20 pM; sufficient for anticipated normal serum concentrations. I then synthesized normal and heavy-labelled target peptides to facilitate accurate quantification by isotope dilution.

However, for measurement by LC–MS, P-III-NP needs to be separated from serum (or blood matrix), as other abundant blood proteins (e.g. albumin) heavily suppress ionization preventing measurement by MS. Experiments revealed that even 0.4 % of albumin, >107 times basal P-IIINP concentration, prevents measurement. I used immunocapture to enrich serum P-III-NP, then split the trimeric covalently bound complex into monomeric strands and digested these into the target peptides for LC–MS quantification.