The power of proteomics

Renowned researcher Dr Valerie Wasinger has been at the forefront of proteomics research since the inception of the field in 1995. Her recent work has led to a patent regarding the enrichment of low mass proteins for inflammatory bowel disease (IBD) diagnosis and monitoring. The application of these ideas for better management and treatment of IBD was the focus of her presentation at the 23rd Annual Lorne Proteomics Symposium.

The etiology and cure for IBD are uncertain, said Wasinger, who is currently based at the Bioanalytical Mass Spectrometry Facility (BMSF) at the University of New South Wales’ Mark Wainwright Analytical Centre.

“Measures relating to disease activity, permeability and inflammation are available but are limited in their ability to measure ‘clinical remission’, a newly accepted gold standard for treatment of this condition. Scientists and clinicians are embracing the concept of intestinal epithelial barrier integrity and its role in the pathogenesis and natural history of IBD.”

IBD, proteomics and collaborative research

“Peptide biomarkers from the low-mass-plasma proteomes have been identified as significant players in the diagnosis of IBD, the differentiation of active disease and remission, and remission in healthy individuals. These markers have been quantitated using MRM. Binding partner studies show a novel relationship to endocytic signalling, lipid metabolism and actin nucleation, and additionally correlate to the ‘tissue integrity’ of leaky-gut IBD patients.

“Modulated proteins in patients with ongoing intestinal damage may be able to predict for relapse and the need to escalate treatment. Markers which can be translated into treatment management able to measure repair of leak, restitution and epithelial cell healing are being sought to manage IBD.

“Currently, I’m working on the proteomics of endothelial tissue integrity and barrier function in the context of IBD in conjunction with my collaborators at Concord Hospital, including Professor Rupert Leong. We have had success identifying biomarkers of IBD that hold true for diagnosing those that are also in disease remission. Now we are expanding this study in the ever-shifting IBD landscape to understand the role of these markers in the context of gut tissue integrity. Dysfunction of the endothelial single cell layer, paracellular leak and cell loss is a prominent focus of many illnesses including IBD. Managing this dysfunction is now the main goal of treatment in IBD with evidence showing that clinical remission can be achieved.

“Having expertise across diverse disciplines (clinicians and researchers) makes this project absolutely relevant. I think that the drive to translate basic proteomic research into clinical outcomes has been overlooked. It requires more than having a hypothesis and proving a point. There has been a huge gap between basic research outcomes and the point where industry wants to partner in your research.

“It’s the place that’s difficult to fund because it has lost its novelty — if you have published. And it requires you to move outside your comfort zone (new technologies and regulatory expertise). There is risk involved, perhaps sufficient to deter individual groups from proceeding. The perfect scenario for the valuable transfer of knowledge from bench to clinic involves a marriage of different disciplines including practical patient care and laboratory research. A facility such as BMSF is the perfect environment to foster these long-term research relationships.”

From bench to clinic

The path from the laboratory to a clinical outcome is long and hard. Wasinger acknowledges that funding, as with all research, remains an ongoing issue. “Global cuts in the research dollar, changing legislation and the high cost of infrastructure and maintenance of that infrastructure are especially challenging to the field of proteomics as researchers realign themselves and establish new funding opportunities for discovery research. From a facilities perspective, the scientific landscape needs to foster long-term projects with a need to recognise the risk inherent for translatable research. The current environment is one fostering research with as little risk as possible.

“Access to expertise and infrastructure is also increasingly in demand as a consequence. This is why many universities are supporting facilities such as BMSF, which become a hub of expansive research experience across all disciplines and proteomic technologies. In association with academics, researchers and industry, these hubs are generating IP, innovation for the next proteomic generation. The fostering of facilities, infrastructure and know-how is a model adopted by many universities.”

Analytical facilities are the correct path forward and often intellectual collaboration provides so much more than a single isolated research lab can generate, suggested Wasinger.

“The space between basic science and patient treatment is in need of transformation. It is complex and there is a huge discrepancy between the initial outlay in resources and effort versus the success of markers in clinical practice. Proteomics is not directly transferable to clinical practice. The reason for this is that basic research is vastly different to the regulatory diagnostic requirements for clinical assay or assays used to monitor disease progression and inform on treatment. Proteomics is becoming more robust in that quality research is recognised for precision and specificity, and as labs routinely monitor and implement quality control and recognise clinical requirements this will aid in reproducibility as well as begin to bridge the gap between bench and clinic.

Personalised medicine

In time, this will allow the full power of proteomics to be utilised in the field of personalised medicine, said Wasinger.  The promise of personalised medicine has received much attention in recent years and many presume that new fields of research like proteomics will have a major impact on this arena.

“Personalised medicine is just a fancy label denoting that we don’t understand enough about a system. The goal of personalised medicine is far more noble; to have in place a road map of all genes, proteins and metabolites to predict every possible disease or treatment scenario, and to use this to inform on treatment and care at a group or individual level rather than a population level. This would allow for the stratification of patients based on evidence. But that noble goal requires a huge investment of money and time.

Technological advances

“The tools used in proteomics are a powerful way to observe all players at the protein level contributing to disease pathways. Hence its emergence and acceptance into translatable clinical settings will drive the proteomic market into the future. Technology-enabled proteomic products are finding applications in diagnostics, health monitoring and therapeutic/drug discovery. This is mainly propelled by advances in mass spectrometry, but also in bioinformatics and the downstream technologies and increasing uptake of micro-array technologies in an already proven bench to clinic pipeline. An increase in the acceptance of user-friendly and cost-effective devices that enable diagnostic assay and measurements at the clinical level is allowing the life sciences to expand into the proteomic domain in addition to the genomic arena.”

Dr Wasinger’s career progression has been atypical but highly rewarding.

“I’m not your typical academic. I am part of the UNSW Analytical Facility. A facility that develops the methods, maintains the high-end tools and are applications specialists. I love my work — I have the best job in the world. This role allows me to work on topics as diverse as IBD biomarkers to sexing ancient human remains and everything in between.”

Curious about the world

Growing up, Dr Wasinger was a fan of science-oriented TV shows like The World Around Us, The Curiosity Show and especially, David Attenborough. “It was the tenacity of life, the unassuming simplicity of ‘being’ and the satisfaction of discovering the meaningful connection in a background of seemingly unrelated things that drew me to studying science and biochemistry and microbiology at Sydney University. But it took a revolution in genomics and a parisitologist with a lot of soul to cement the love of research. The forecast of a lifelong structural study of a single molecule had changed to the possibility of understanding all the connections, all the (proteins) players at the one time. That seemed like a panacea to me. I was in.”

Dr Wasinger is recognised in the field of proteomics in Australia and internationally. In the early 1990s, she became involved in groundbreaking research into the new field of proteomics, co-authoring the paper in which Marc Wilkins first coined the term.

“I was in the right place at the right time — at the cusp of the genomic sequencing revolution in the early 1990s, and the release of entire genome data into public databases. Wolfgang Paul had just won the Nobel prize for the ion trap technique (1989) and Fenn, Tanaka, Karas and Hillencamp were about to revolutionise the very tools that so much define the field today. Our group at Sydney University was working with Macquarie University and UNSW on the techniques (such as 2D-gel electrophoresis, mass spectrometry and amino acid analysis and database search algorithms/tools) as well as the fundamental concepts that defined and created an entirely new field of research — proteomics. Notably, researchers from a number of Australian universities contributed to its creation.”

Proteomics continues to be a field driven by Australian scientists and the Annual Lorne Proteomics Symposium has become one of the largest internationally recognised events in Australia in this field.