Science

Proteins, Proteomes and Proteomics

Proteins are the main action molecules of life, the enzymes like amylase in your saliva that breaks down starch in your food into smaller pieces, or troponin in your heart regulating contractions, or the structural components like collagen in your connective tissue, actin/myosin in your muscles, elastin in your skin, histones packaging and protecting DNA in your nuclei and regulating gene expression, or immunoglobulins on the lookout for your bacterial and viral invaders. If you have been diagnosed with a disease, chances are that measuring quantities of different proteins in the blood, urine and via other tests were important factors to come to this conclusion, just like these measurements are going to be important to assess your recovery.

A proteome is a collection of proteins present in a particular space and during a particular time point or time period. In living organisms a proteome usually represents all proteins expressed and functioning in a particular ‘place’ (spatiotemporal unit) but this unit can be interpreted on many levels: a single cell, groups of neighbouring cells, groups of types of cells, a volume of bodily fluid like saliva or blood or urine, a particular tissue like muscle tissue, a particular organ like kidney, a particular organ system like the nervous system. Concerning the state of the proteome it can be a diseased proteome from a tumour or a healthy proteome from healthy individuals or a healthy control proteome from ‘normal’ neighbouring cells of a tumour.

Proteomics measures proteomes. Sometimes the term is over-used and un-substantiated when only a couple proteins are detected. I’d say the minimal set that qualifies for a proteome is higher than that. Proteomics might cover different methods and our choice and expertise is the only unbiased and high-throughput method that has been thoroughly validated many times over in the last decade and it is mass spectrometry proteomics. Proteins can be broken down into separate peptide sequences, consisting of tens of amino acids as basic building blocks. The mass spec machine measures peptide intensities and sequences peptide components in consecutive MS runs. Doing so it avoids the pitfalls of other type of measurements where there is a clear and present danger of cross-reactivity yielding false positives hard to control. The mature bioinformatics part of mass spec proteomics makes sure to infer back the identity and quantity of the proteins present in the sample in a reliable way. This way mass spec proteomics is the sound and thoroughly validated choice to measure proteome-wide protein abundances and also as a bonus, proteome-wide protein modifications, that are so important in regulation.

The scientific problem of understanding biological aging is two-fold: i., we want to understand what processes change with age and how and ii., we want to understand the disconnect between chronological and biological aging. Both are needed in order to develop robust interventions to slow or to stop particular negative aging processes.

Measuring changing protein quantities throughout our life trajectories will have a lot to add to unfold these problems. Let me highlight two fresh studies to show accumulating evidence of proteomics in delivering aging signatures. The first study [1], from last year, by the Wyss-Coray lab at Stanford, used 4000+ blood samples, from people aged 18-95, measuring ~3000 proteins to show 3 jumps in the quantities of plasma proteins at different ages indicating bigger changes in the life trajectory. Also it showed 373 proteins highly accurate in predicting chronological age. The second study has been published couple weeks ago by the Schilling Lab in the Buck Institute, and they have built a proteomic atlas of soluble and secretory proteins associated with cellular senescence, one of the hallmark aging processes [2].

Notes:

[1] Closed access paper in Nature Medicine: Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, Moran Losada P, Berdnik D, Keller A, Verghese J, Sathyan S, Franceschi C, Milman S, Barzilai N, Wyss-Coray T. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019 Dec;25(12):1843-1850. PMID: 31806903.

Complete draft version available over at biorxiv: https://www.biorxiv.org/content/10.1101/751115v1

[2] Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T, Rao C, Holtz A, Shah S,

Sharma V, Ferrucci L, Campisi J, Schilling B. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020. Jan 16;18(1):e3000599. PMID: 31945054 https://www.ncbi.nlm.nih.gov/pubmed/31945054