While the genome contains a list of instructions for the cell written in DNA, the proteome comprises all the proteins within a cell or organism that are coded for by genes within the genome. The proteome is in effect a record of all the proteins that a cell needs to function in a certain state and therefore contains a lot of useful information. By studying and comparing the proteome in healthy and disease states, researchers hope to understand the changes that are either a cause or a result of disease.
Clinical proteome analysis - hot or not?: view the full infographic here
Proteomic information, gathered from patient samples such as tissue, blood, saliva or urine, could underpin more personalised clinical management of disease. The proteome is in constant flux – changing according to the health or progression of disease in the body – suggesting possibilities for earlier detection of disease, disease stratification, and precision monitoring of a patient’s response to treatment. It could also indicate whether an individual patient would benefit from a specified treatment or other intervention. One goal of clinical proteome analysis is to seek out specific biomarkers, such as single or groups of proteins that indicate disease states. This type of information could also be useful to those interested in drug discovery, identifying drug targets and then using proteome analysis to measure in real-time how new compounds are performing.
However to do any of this, we first need to categorise an d understand the clinical proteome - an intricate biological and technical challenge. The proteome is complex: there are at least ten times as many proteins within the human body as there are genes – at least 250,000 proteins coded for by around 21,000 genes. This is because most proteins undergo post-transcriptional modifications after they are made, where chemical alterations are made to the basic protein to change its structure and function depending on what the cell needs.
The proteome also varies between different cells and tissues, depending on their function, and is a dynamic system that is constantly changing according to the needs of the organism, physiological state or external factors. For example, protein molecules form complexes with other proteins (or other types of molecule) or change structure when they bind to the cell membrane. This complexity is keeping clinical proteome analysis very much in the research-only arena for now.
The complexity challenge is compounded by the huge range of concentrations of proteins in the body which are pushing the limits of the technology used to measure proteins – for example, the blood protein albumin is around a billion times more concentrated than the immune system protein interleukin-6. The most commonly used technology, mass spectrometry, is being extensively developed, but further innovations are needed to accurately map proteomes. One development in mass spectrometry technology, SWATH-MS, is a more accurate and higher-throughput method that generates protein maps, combining protein discovery with the ability to accurately compare protein quantities between samples. It is a promising technology that is being actively developed in research studies, but a lot more work needs to be done particularly on the analysis methods used on SWATH-MS data.
A proteomic future?
Clinical proteome analysis is a challenging and complex area of research which is being actively pursued. One such initiative, the MRC-funded Clinical Proteomics Centre for Stratified Medicine in Manchester, will be using SWATH-MS proteomics approaches to study conditions such as rheumatoid arthritis, psoriasis, lupus and cancer.
Within the next five years we should see progress on the technical challenges, such as an improvement in the sensitivity of mass spectrometry machines. More immediately, with the research programmes gathering pace and starting to collect data, it is likely that more conventional proteomic methods such as the lower-throughput mass spectrometry technologies and antibody or tissue microarrays will yield clinically useful findings. For now, it is currently too early to say how clinical proteome analysis will be viable or useful in a clinical context.
Laura provides support for a variety of projects at PHG Foundation, including infectious disease genomics.More about Laura