Why is proteomics missing from precision medicine?
Accounting for the influence of genetics, lifestyles and environments in disease treatment and prevention is the goal of precision medicine. Yet, despite its potential, proteomics remains largely absent from this emerging field, says Liam Bell, a proteomics coordinator at Diplomics.
Recently, a team of researchers from the University of Cape Town developed a genital inflammation test (GIFT) for HIV prevention. The test detects markers of vaginal inflammation indicative of sexually transmitted infections (STI), which increase the risk of HIV acquisition and other adverse health outcomes even in the absence of symptoms. The innovation was made possible by proteomics – the study of proteins, collectively known as proteomes. A proteome encompasses all proteins expressed in a cell, tissue or organism at a certain time.
“Proteins are your life’s workforce,” says Liam Bell, a proteomics expert at DIPLOMICS, a national research infrastructure platform that provides cutting-edge protein analysis technologies to South African scientists. Proteins orchestrate and direct processes from the cell level right up to the level of complex systems like the immune system. They adjust their structures and functions to react to pathogens, manage cellular processes, and perform countless tasks vital to life. Analysing the type and amount of proteins in a particular sample (blood, tissue, etc) can paint a picture of what’s happening in the body at a particular time.
In the case of bacterial vaginosis or STIs, the immune system sends protein messengers, or cytokines, to the vagina to initiate an inflammatory response. By detecting these cytokines above certain levels, the GIFT device can screen for asymptomatic STIs and BV. In low- and middle-income country settings, where accurate molecular testing is often unavailable, GIFT could significantly increase women’s access to critical treatment.
The GIFT device is just one example of how proteins can guide clinical decision-making. Other proteomic research focuses on diagnosing, monitoring and treating cardiovascular disease, neurological disorders, kidney disease, autoimmune conditions and diabetes.
Recently, Oxford Population Health researchers discovered 618 blood proteins linked to 19 types of cancer. These protein biomarkers could predict cancer in patients up to seven years before diagnosis, enabling better and earlier treatments.
Proteomics can also find unexpected uses for existing drugs, significantly reducing the time and costs involved in drug development. For instance, Disulfiram is a promising new cancer treatment that was first approved to treat chronic alcoholism. The drug Rapamune® (sirolimus), developed by Pfizer to prevent organ transplant rejection, recently became the first drug approved for a rare lung disease.
The missing middle
Rapid advancements in genome sequencing technologies have accelerated our understanding of the human body, helping to explain different disease prevalences across population groups. Perhaps for this reason, genomics tends to take centre stage in precision medicine. Precision medicine aims to select diagnostic, prevention and treatment approaches for patients based on biological and environmental factors. Variation at the protein level can help to explain why individuals respond differently to diseases, lifestyle choices, and other factors.
“There’s a huge amount of variation in biology, and there are different ways to look at what that variation is,” says Bell. “So you might look at the genes, you might look at the transcripts, you might look at the proteins, or you might look at the metabolites (a diverse class of small molecules involved in metabolism).”
At the molecular level, DNA (Deoxyribonucleic acid) is the body’s genetic blueprint, storing the instructions for all cellular functions. Specific sequences of DNA, called genes, are transcribed into RNA (Ribonucleic acid), which carries these instructions to the cell’s protein-making machinery. In a process called translation, the RNA sequence directs the assembly of amino acids into proteins. While the genome is relatively static, proteins are dynamic and actively respond to changes in the environment.
Because proteins play an active role in disease progression, clinicians often rely on protein-based tests – such as the GIFT device – to guide their clinical decisions. This suggests that promoting a deeper understanding of proteins’ roles in the body could accelerate advances in precision medicine.
New opportunities for proteomics
While proteomics remains the ‘smaller sibling’ of genomics, Bell and other proteomics experts are beginning to change that. DIPLOMICS’ D-CYPHR platform, a resource for analysing and interpreting proteomic data, aims to accelerate precision medicine by helping local researchers integrate proteomics into their work. The DIMPLOMICS team recently launched the high-impact programme Nngwe to focus on rare diseases. The programme will employ multi-omics approaches to identify underlying causes of rare diseases and guide the development of new therapies.
Until recently, proteomics’ role in precision medicine was curtailed by the complexity of protein analysis and the time it took to analyse a proteome. A single blood or tissue sample could contain thousands of different proteins at varying concentrations. Before being measured, proteins must be fragmented into smaller particles called peptides. Then, the peptide multitudes are gradually fed into a mass spectrometry (MS) machine, which ionises and effectively weighs them to determine the type and abundance of proteins. The process might take minutes to hours for a single sample. However, advances in MS technology now allow researchers to process up to 180 samples daily, significantly expanding their ability to look for new disease biomarkers.
Bell and his team hope investments in local skill and expertise will finally see proteomics stepping out of genomics’ shadow. By integrating proteomics with genomics and other ‘omics’ approaches, South African researchers can empower healthcare workers to provide timely, individualised healthcare.
