Vera Ignjatovic,University of Melbourne, Australia
Gil Omenn is one of the founding members of the Human Proteome Organization, has led the Plasma Proteome Project from 2002 through 2010, and chaired the Human Proteome Project from 2010 through 2018. He also served as President of the U.S. HUPO. Gil is a Distinguished University Professor of Computational Medicine & Bioinformatics, Internal Medicine, Human Genetics, and Public Health at the University of Michigan and a member of the U.S. National Academy of Medicine.
Human Proteome Project
What would you like to see happen in the HPP over the next 3 years?
Gill: I would like to see a coalescence of subsets of the C-HPP teams and subsets of the B/D-HPP teams to accelerate scientific progress on the overriding aims of the HPP: (a) completing and annotating the protein parts list and (b) making proteomics an expected part of all multi-omics studies in biomedical research. I am keen to see the four resource pillars drive collaborative studies across antibody profiling, mass spectrometry, bioinformatics, and pathology. And I would like to see significant growth in numbers of participants in the HPP and the HUPO World Congress.
What do you see as the role of the HPP in the future progress of proteomics? Gill: The HPP has worked openly with proteomics researchers globally, with an emphasis on quality of data, sharing of complete datasets and metadata, and metrics for the annual progress on the “draft human proteome”. I hope we will see much more extensive application of quantitative proteomics and systems biology across all the fields of medical research.
Do you see the HPP Knowledgebase as critical for the future of the HPP? Gill: Yes, indeed. The combination of neXtProt, PeptideAtlas, ProteomeXchange/PRIDE, and interchange with other resources internationally has greatly accelerated the field of proteomics. Data Quality Guidelines for Mass Spectrometry and the International Working Group on Antibody Validation are critical for credibility and progress in the field and in the HPP. Reliable, fully shared and reconfirmed data with tools like the TransProteomicPipeline, neXtProt uniqueness mapper, the Universal Spectra Identifier, and the SRM Atlas and Popular Proteins lists can accelerate biological and clinical applications from the HPP and the community at large.
What is your advice to early career scientists? Gill: I am proud of the significant commitment to Early Career Scientists in the development of the HPP and especially the B/D-HPP. I urge young colleagues to ask major questions about the field of science they choose, to be alert for relevant stimulation from other fields of science, to connect research with unmet needs in clinical medicine, and to master the technical aspects of their scientific work. Always make an effort to build personal relationships and find ways to enjoy your chosen work. Make sure your potential mentors are up-to-date in the field and able to provide cogent guidance on the research you hope to undertake.
Where do you see the gaps in technologies? Gill: One of the persistent gaps is the separate use of antibody profiling and mass spectrometry; we need studies that deploy both approaches on the same specimens. In the field of epigenetics, there is a chasm between analyses of DNA methylation and analyses of histone marks. The latter is often neglected by the genomics folks. This requires links between DNA and protein sample prep and analytical methods and the researchers. There is a similar gap between evidence of splice isoforms in the RNA-Seq transcript data and in direct studies of proteins. Alternative splicing is one of the most remarkable features of the evolution of multi-cellular organisms, with their intron/exon gene structures. It is shocking that many researchers lump together the splice isoforms from the same gene and presume that they are functionally the same; in many cases, we know that is not true. Finally, single-cell transcriptomic and CyTOF proteomic studies are proving feasible and valuable in cancer biology and developmental biology.
What do you see would be the role of proteomics in the clinic? Are devices such as MasSpec Pen possible as future implementations in the clinical routine? Gill: We need high throughput, reasonably sensitive, moderate cost assays combined with specific biomarkers to generate actionable data for clinical decisions and for epidemiologic studies, as well. There has been progress, especially in Europe, with MS for microbial diagnoses and inherited disorders in clinical settings.
The MasSpec Pen has generated a lot of press attention during the past 2-3 years. Articles from Hungary in 2013 and from University of Texas/Austin in 2017 in Science Translational Medicine have reported an automated, biocompatible handheld mass spectrometry device for rapid, non-destructive diagnosis of human cancer tissues. The MasSpec Pen enables controlled, automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules within a few seconds, which is then delivered to the mass spectrometer for molecular analysis of proteins and metabolites. The usefulness depends on the quality of the cancer biomarkers assayed and the rapidity of analysis. The device is still in the clinical development pathway with results reported from studies on mice and on cells in vitro. I have no experience with this device, which may not yet be FDA-approved. The concept for its use in surgical removal of cancers is to sample the margin of the surgical field and rapidly analyze a few key proteins in the hand-held device.
What/Who was the largest influence in you moving your career into proteomics? Gill: I became interested in proteins as an undergraduate at Princeton; actually, I had problems growing and isolating sufficient protein from the acellular slime mold Physarum polycephalum, so I ended up doing electron microscopy of its previously unrecognized cytoplasmic latticework! At Harvard Medical School with a young faculty member Tom Gill III and during a summer research experience at The Weizmann Institute of Science with the inspirational Ephraim Katzir (later the President of Israel), I worked on synthetic polypeptides as models of proteins. Then, for my military duty during the Vietnam War, I had a wonderful opportunity to work at NIH with Christian B. Anfinsen on structure and function studies of staphylococcal nuclease. He received the Nobel Prize in 1972 for the concept and the compelling evidence that the amino acid sequence of proteins determines the 3-dimensional folding and function of each protein. After decades of work in human behavioral genetics and eco-genetics, and leadership roles in government, public health, and healthcare, I returned to proteins in collaboration with Sam Hanash with the founding of the Human Proteome Organization in 2002. For those interested in my personal journey, here is a link to my U of Michigan Distinguished University Professor Lecture about “Paths Less Travel’d” (a phrase from Robert Frost, who taught at the U of M), video link to my DUP lecture.
What was the most exciting scientific finding of your career? (The eureka moment!) Gill: Clinical: As a 4th year medical student, the recognition of a syndrome of primary immune deficiency affecting 12 children in one large kindred, later named “Omenn syndrome” by McKusick of Johns Hopkins and then cured by bone marrow transplantation by a French team and linked to Rag1/Rag2 genes.
Mechanisms: The recognition that cancers of non-endocrine organs, like lung, sometimes produced hormonal disorders not due to “disordered protein synthesis” but by activation or de-repression of the corresponding gene for the polypeptide, which is available in every cell type and would yield exactly the same sequence as the normal hormone.
Public Health: The shocking finding that the combination of beta-carotene and retinyl palmitate, hypothesized to prevent lung cancers and cardiovascular deaths, actually caused more cancers and more CVD deaths in our beta-Carotene and Retinol Efficacy Trial (CARET).
How do you keep a work/life balance? If there is such a notion? Gill: Yes! I have always enjoyed my studies and my work, as I do currently, while pursuing a variety of interests that broadened my social interactions and made for a stimulating life. I played clarinet in the band, oboe in the orchestra, sax in the dance band, and piano lots of places (still do). I played intramural tennis at Princeton and Harvard Medical School, and remain competitive in doubles tennis. I have long been active in science policy matters and political campaigns, as well as serving in the federal government as a White House Fellow at the Atomic Energy Commission, as associate director of the White House Office of Science & Technology Policy and the Office of Management & Budget, chairing the Presidential/Congressional Commission on Risk Assessment and Risk Management, and serving on the Scientific Management Review Committee for the NIH, as well as boards of cultural organizations. My wife, Martha Darling, whom many of you have met, also has a wide range of national and international activities, which we often enjoy together.
What do you consider the major achievements of the HUPO Human Proteome Project (HPP)?
Gill: 1. The HPP commitment to high quality science in proteomics experiments and data analysis. This includes the development and wide utilization of the HPP Guidelines for Interpretation of Mass Spectrometry Data (v2.0, JPR 2016) and the encouragement of generations of improvements in the underlying technology platforms.
2. The placement of neXtProt, PeptideAtlas, and Human Protein Atlas at the center of the proteomics world.
3. The creation of ProteomeXchange in conjunction with the European Bioinformatics Institute and PRIDE to register and make widely available the primary data and meta-data from all proteomics experiments, incorporated into the HPP Guidelines.
4. The organized effort to apply standardized reanalysis of all MS-based proteomics datasets at PeptideAtlas and curation of multiple kinds of protein studies at neXtProt to progressively complete the “protein parts list” for the human proteome. As of January 2018, 87% of predicted protein-coding genes (17,470 proteins) were rated as having protein evidence PE1 (of a total of 19,656 PE 1+2+3+4). This percentage continues to rise, with leadership from the Chromosome-centric C-HPP and the KnowledgeBase resource pillar of the HPP. Each year the HPP published the “Metrics paper” in the Journal of Proteome Research with progress from the entire community.
5. The development of the SRM Atlas to expedite targeted proteomics for quantitative biological studies throughout the life sciences by providing spectra from synthesized, predicted proteotypic peptides of nearly every predicted protein.
6. The use of bibliometric analyses to identify the most investigated proteins (“popular proteins”) by organ and disease category and connect those research communities to the SRM Atlas as a guide to quantitative targeted assays of those key proteins and their pathways and networks, led by the Biology and Disease-based B/D-HPP.
7. The tissue-specific and intracellular localization of expression of proteins with immunohistochemistry/ immunofluorescence, correlation with organ-specific transcript expression, and quality assurance of antibody specificity by Human Protein Atlas (Antibody-Profiling resource pillar of the HPP).
8. Continued effort to make proteomics an obligatory component of multi-omics research protocols, recognizing that crucial properties of proteins—dynamics of abundance, post-translational modifications, and splice isoform variants—cannot be predicted or detected at the gene or transcript levels. Complemented by the C-HPP-led initiative to find evidence of function for the 1260 PE1 proteins lacking specific functional annotation.
9. Multiple efforts to engage, mentor, and highlight research from Early Career Researchers, the future of the field.