Is systems-level proteomics ready for a seat at the table with our genomics colleagues, as a full partner contributing to large-scale biological research, translational research and personalized medicine initiatives? Up until very recently, the answer would have been “no”, but an intriguing new commentary suggests that the answer may now be “YES!”
In the Beginning…
Proteomics came out of the closet when John Yates, a pioneer in proteomics, demonstrated in 1999 that modern LC-MS instrumentation could identify several hundred proteins per day from a small amount of cellular material. With continued innovations in mass spectrometry technologies over the last 15 years, we saw the the publication of the first draft of the human proteome, simultaneously published by two independent research groups lead by Dr. Akhilesh Pandey and Dr. Bernhard Küster. Based on Orbitrap technology, these were truly massive proteome profiling efforts with 16,857 LC-MS runs, 1.1-billion peptide spectrum matches (PSMs) generated from 60 tissues, 13 body fluids, 147 cell lines and ~1,300 affinity purifications.
So - what have we learned? It can be postulated that the human proteome is represented by 10,000–12,000 ubiquitously proteins which are largely the same between different tissues, with a few proteins exclusively expressed in some tissue. However, except for a near comprehensive catalogue of proteins which is undoubtedly a valuable reference point we have little biology to show for at this point. Why?
Proteomics Is Not Genomics
Proteomics is not genomics where a single, whole genome sequencing experiment provides a relatively accurate picture of the genomic aspects of biology. Because proteomics is (was?) complicated, expensive and time-consuming, we have been forced to limit the number of samples we process and restrict ourselves to a static view of biology. We have been looking at snapshots, when we really want to see dynamics as biology changes over time, across many samples. We want to see the important differences between closely related biological states, such as the stages of cellular development and differentiation or the cellular response to therapeutic intervention at a protein, PTM, or even proteoform level. And we want to quantify them.
The Coming of Age of Proteomics
Broad, systems-level proteomics is coming of age. Hand-in-hand with innovations in mass spectrometry, multiplexed quantitation through isobaric labeling techniques further increases throughput in large-scale protein analysis, along with improvements in sample processing – all leading to improving the depth, speed and cost of detailed, quantitative proteome profiling. These tools have to be comprehensive and reproducible and, more importantly, integrate well with other techniques (genome sequencing, expression profiling, metabolomics, microscopy, etc.) to create a comprehensive understanding of biology.
Has proteomics caught up enough with genomics and is it ready for a seat at the “systems” table? Can it add significant new insights into biology – reliably, quantitatively, and on a large scale?
The answer is YES, systems-wide proteomics has come of age and is ready for prime time.