Mapping the Human Proteome: A Conversation With Professor Emanuel Petricoin
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This year, science celebrates mapping 90% of the human proteome, an endeavor that has been achieved by the Human Proteome Project (HPP). Technology Networks explored the journey to this successful feat by speaking with Professor Emanuel Petricoin.
Petricoin is a professor and co-director of the Center for Applied Proteomics and Molecular Medicine at George Mason University. Petricoin's research focus is on the development of cutting-edge microproteomic technologies, identifying and discovering biomarkers for early stage disease detection, developing novel bioinformatic approaches for protein-protein interaction analysis and creating nanotechnology tools for increased analytical detection, drug delivery and monitoring. He is one of the founding members of the Human Proteome Organization (HUPO).
Molly Campbell (MC): As one of the co-founders of HUPO, how do you feel about the news that ~90% of the human proteome has now been mapped?
Emanuel Petricoin (EP): It’s a great achievement! One of the major objectives when we first launched HUIPO was to simply understand the nature and existence of the human proteome. But the development of the catalogue is really only the beginning, and of course those last 10% may be exceedingly difficult to categorize and uncover; they are the lowest abundance analytes which may contain the most important biochemical information as far as human disease and the “biomarkers” that everyone is after are concerned.
We need to couple new advances in sample preparation to concentrate and be able to bring them into the sensitivity range of mass spectrometry. Moreover, and critically, there are a massive number of post-translational modifications (PTMs) of the proteome and it is really these PTMs that make all of the difference in biology and disease. We really don’t have a clue as to that proteome! This is what is difficult about proteomics, it's not simply a list of proteins – but it is their expression level, location, activation state and “who is talking to who”, as the proteome is a dynamic, physically interconnected network of interacting molecules with fine-tuned orchestration of location and amounts. Even with this great achievement, it is simply a list – and like a list of parts for a 747 aircraft, it doesn’t tell you anything about how the aircraft is put together, how it operates and most importantly how to fly it. But, before you can do anything, you have to know the parts list. This is what the field has achieved, and it is fantastic – but just a start – we need to take the parts list and construct the instruction manual, and that is going to take a huge amount of continued effort.
MC: The blueprint of the human proteome comes almost twenty years after the completion of the Human Genome Project. During this time, do you think attitudes towards the proteomics field have changed? If so, how?
EP: Absolutely. I think there is a real and important shift to proteomics now – a “beyond genomics” orientation. I think some of this is the limitations that are being seen in the narrow actionability landscape of genomics in many diseases, notably cancer, as well as recognition that genomics-stratified patients do not effectively capture many of the responders and non-responders in many targeted therapy efforts. We still need a massive injection of new discoveries of highly sensitive and specific biomarkers for disease detection. HUPO’s efforts here provide that catalyst and I think you are seeing more and more examples of biomarker signatures comprised of both genomic and proteomic markers for more accurate and sensitive disease detection. Moreover, I think that there is a re-focused interest by the field of molecular diagnostics and precision medicine on the potential for true synergy between proteomics and genomic based profiling for better clinical outcomes and better biomarker signatures for detection and treatment of human diseases.
MC: The HPP is divided into the C-HPP and the B/D-HPP. What are each of these subcategories, and why is the project divided in this way?
EP: These efforts underscore the unbelievable complexity of the human proteome- in fact it illustrates the fact that a simple parts list, while important, is not even close to being enough; as they say, while the DNA is the information archive, it’s the proteins that do all of the work – and it's all about what proteins are expressed, how much is expressed, where they are expressed, at what time they are expressed, in what isoform they are expressed and to what levels (phosphorylated, myristolated, glycolsylated etc.) and in what cell type are they expressed. You may actually argue that there should be a further subdivision of other sub-categories within each of the disease subgroups in the B/D -HPP and C-HPP categories!
MC: Confident detection of the human proteome has risen from 69.8% in 2011 to 90.4% in 2020. How has this been achieved?
EP: Massive improvements in mass spectrometry instrumentation and mass accuracy and the computational informatics side together have led to this along with better enrichment and fractionation methods for better sample input integrity.
MC: Are there some proteins that we may never be able to map? If so, why is this?
EP: Perhaps it will take quite a while, but I can't imagine that we can be so dogmatic to say NEVER- science is always improving and getting better and better. Right now, it is a product of these 10% being extremely low abundance and having extremely short half-lives and mass spectrometry still not being analytically sensitive enough to “see” these markers.
MC: How can the data from the HPP be used in a clinical context? What barriers exist to translating the research from lab to the clinic?
EP: Well, that is the elephant in the room, isn’t it? The same was said after the human genome was mapped. Patients stood at the announcement and said so what? How does this information and list of genes help me today or tomorrow with my cancer? The same can rightfully be said here – how does a simple list of proteins help a cancer patient today? The field needs to be very transparent and thoughtful about how it conveys the impact of the achievement to everyday impact on humans and society. It will take years and decades more effort to take the aggregate of this proteomic data to translate into well performing clinical grade diagnostics/therapeutics that impact patients at the bedside – and it is not like we didn’t already have most of the 90% already – much of this has been had for years and we still haven’t taken a vast majority of it to new biomarkers/treatments/drug targets that physicians use to manage care.
Emanuel Petricoin was speaking to Molly Campbell, Science Writer, Technology Networks.