By Darlene Solomon, PhD, and Stephen R. Pennington, PhD

The 21st century has witnessed remarkable advances in molecular biology. Not only are these advances transforming our understanding of life’s most fundamental processes, but they are also starting to enhance our well-being. Proteomics, the generation of comprehensive protein expression profiles, has played a pivotal role in this journey, expanding our understanding of vital biological processes and opening new possibilities in precision medicine and targeted therapies.

Stephen R. Pennington, PhD
Stephen R. Pennington, PhD

The success of these achievements goes hand in hand with collaborations between technology providers and visionary scientists. One such collaboration exists between Agilent Technologies and University College Dublin (UCD). When the collaboration was initiated, the principals included Darlene Solomon, PhD, then Agilent’s chief technology officer, and UCD’s Stephen R. Pennington, PhD, professor of proteomics.

Unleashing the power of the life sciences

Over the past several decades, many technological and commercial advances in the life sciences have been enabled by advances in the physical sciences, specifically, advances in electronics, computers, and internet-based technologies. And the advances in life sciences have, in turn, enabled advances in multiple fields. One such field, Solomon pointed out, is precision medicine. With its ability to generate individualized healthcare insights from molecular information, precision medicine is already making significant strides, particularly in oncology.

“Our understanding of cancer, the disease itself and how to treat it, is expanding with new layers of biological insights,” Solomon explained. “This includes additional molecular information, such as proteomics and metabolomics, and the interconnectedness of cellular pathways and cellular communication.”

Solomon suggested that these advances, from the physical sciences onward, can be seen as a series of waves. “We are on the cusp of the next wave,” she continued. “Our understanding of biological information and processes will increasingly impact industrial biotechnology and cellular manufacturing. This promises the ability to reprogram biological cells for practical purposes, paving the way for a bioeconomy and sustainable alternatives to petroleum-based manufacturing.”

Darlene Solomon, PhD
Darlene Solomon, PhD

The idea that scientific advances could succeed each other was also taken up by Pennington. He suggested that the enabling technologies for proteomics could be seen in this context: “They have allowed us to undertake the analysis of proteins at a genome scale, rapidly and in a more effective, efficient way.” And by enabling the analysis of proteins at such a scale—not just in protein expression profiling, but also in the mapping of protein interaction networks—proteomics can contribute to powerful applications in human biology and human disease research.

Proteomics, then, has a dual role. It is both a beneficiary and a driver of conceptual breakthroughs and technological advances. As such, it is a key player in the “Century of Biology.”

The hidden world of proteins

Proteomics, as explained by Pennington, is the cataloging of all the proteins that are expressed (or that could be expressed in different circumstances) from the genome in a cell, tissue, or organism. Accordingly, proteomics can deepen our appreciation of proteins as active agents in cells, for example, as pathway elements in cell signaling and metabolic processes. Despite the importance of proteins in cellular functions, proteomics has yet to be as fully developed as genomics.

To help give proteomics its due, Pennington has devoted his career to the subject. As a member of the UCD’s Conway Institute, he was an early participant in the Irish Prostate Cancer Research Consortium, a collaborative effort that unites clinicians and scientists to identify protein and other potential biomarkers relevant to prostate cancer. He has also been president of the Human Proteome Organization and president of the British Society for Proteome Research.

Pennington has led research efforts focused on the mass spectrometry–based discovery, measurement, and validation of protein biomarkers to take them from discovery to clinical utility. These efforts have attracted support from multiple organizations, including Movember, an international agency funding prostate cancer research.

In a recent Agilent case study, Pennington noted that in his research on prostate cancer biomarkers, he decided to focus on blood samples rather than tissue biopsies. Besides being invasive, tissue biopsies often fail to capture the heterogeneity of prostate cancer. However, Pennington admitted that blood samples posed their own difficulties.

“The key challenge in developing a blood-based test is accessing the broad dynamic range of the proteins that are present in serum—and having assays that can cope with that kind of dynamic range,” he stated. “A key step for us has been establishing the Agilent partner lab in which we’ve been able to get really robust, reproducible data.”

Pennington’s team used Agilent’s multiple affinity removal system to deplete the serum samples of high-abundance proteins. Then the researchers used an Agilent HPLC-Chip/MS system to look for proteins that might change. They now look forward to validating a biomarker panel using a cohort of 900 patient samples.

According to Pennington, the biomarker identification approaches that have been developed in oncology research can be applied to diseases other than cancer. He noted that he has studied how psoriasis can progress to psoriatic arthritis. His research in this area is supported by the Hippocrates Consortium, which aims to monitor patients with psoriasis and to identify markers that indicate a higher risk of progression to psoriatic arthritis.

At present, research suggests that around 30% of patients with psoriasis are at risk of being diagnosed with psoriatic arthritis at a later stage (Mease et al. J. Am. Acad. Dermatol. 2013; 69(5): 729–735). By utilizing state-of-the-art proteomics methodologies, Pennington and his team aim to identify proteins that address the unmet needs of individuals with psoriatic arthritis. This research could lead to interventions at an earlier stage and better therapeutic opportunities.

In 2017, Pennington founded Atturos, a spin-out company, to translate research developments from the Conway Institute into commercial products. Atturos indicates that it uses multiple reaction monitoring (MRM), a mass spectrometry–based technique that can selectively quantify compounds within complex mixtures, to measure blood proteins. The company adds that it uses proprietary algorithms to convert MRM data into easily interpretable scores that can guide better decisions for improved patient outcomes.

A step toward the future

Pennington and Solomon also discussed their views on the future of biology and the current challenges in the field. Pennington highlighted the complexity of proteomics, emphasizing the vast number of proteoforms—different isoforms of the proteins expressed from the genome—and the chemical modifications involved. He described the need for new technologies to enable real-time spatial and temporal analysis of all proteoforms. Such technologies would significantly advance the field.

Solomon added that although proteomics is improving our understanding of cancer and autoimmune conditions, it has yet to unravel all the protein-related complexities of living organisms and systems. In other words, challenges remain. To overcome these challenges, Solomon proposed improvements in mass spectrometry workflows, sample preparation, and data analytics.

Immense possibilities

To judge by the comments shared by Solomon and Pennington in this article, the development of sophisticated proteomics applications and the emergence of precision medicine are testaments to the life sciences’ capacity for innovation—the animating principle in this, the Century of Biology. As we bear witness to this awe-inspiring era, the life sciences have become a captivating realm that demands our attention and promises an exhilarating future.

 

Darlene Solomon, PhD, is former Chief Technology Officer at Agilent Technologies and Stephen R. Pennington, PhD, is a professor of proteomics at Conway Institute, University College Dublin.

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