Read more

Appendix 2

New C-HPP Strategy*

1. Revised “HPP Cluster Collaboration Strategy” (2016 version), by Young-Ki Paik, Chair of C-HPP

A. Background and Aims

As the technology in proteomics moves rapidly along with the publication of large-scale competitive publications, it was necessary for us to closely re-examine the direction of ongoing projects and the operation of HPP teams to ensure that we are continually at the forefront in the study of chromosome-based or biology/disease-based proteomics (Fig. 1). In an attempt to introduce some changes in our cooperative consortia operation, the concept of cluster collaboration strategy was initially coined during the 12th C-HPP workshop at Milano 2015 but now being expanded into all HPP area as a pilot case.
Fig. 1. The concept of cluster group collaboration between HPP Initiatives. Once missing proteins involved in various diseases (e.g., cancer, membrane function, reproductive disease etc.) are newly identified, they are annotated by neXtProt and released on the web site. Any interesting investigator will pick up one or some of these newly identified proteins and start characterizing their functions. In practice, the initial findings of missingproteins (MPs) by a C-HPP team may be validated or shown orthogonally, perhaps by antibodies-based approaches, perhaps by SRMs etc. It is anticipated that the B/D-HPP investigators will seize upon these interesting MPs and others that remain under-investigated that may be relevant to a disease process, Thus translation with the B/D group is hoped to be stimulated to develop mechanistic and novel biological insights into a disease leveraged by the new MPs.

The purposes of this cluster group formation included, but were not limited to, (i) stimulating the activity of each team and the work performance of chromosome-based or biology/disease-based proteomics research in a cooperative manner, (ii) effecting a closer working relationship between chromosome teams and other related consortia (e.g., B/D-HPP, Pillars and CPTAC) toward completion of the scientific goals and (iii) strengthening of the research focus of HPP teams using advanced proteomics platform technologies and resources.

B. Approaches

This collaborative strategy will be applied to all areas of the C-HPP first and then extended to other HPP teams, if necessary, during the process of MP discovery and validation, data integration, disease mechanisms and biological studies. Teams can use or share the common resources (cell types, tissues or biological conditions) and technology platform in the hope of ensuring the highest probability of detecting a given protein/proteoforms. With collaborative networks, more efforts will be placed on devising metrics to unequivocally define these newly detected protein/proteoforms.

This cluster strategy plan was accepted unanimously during the PIC meeting at the Vancouver 2015 congress at which we had an opportunity to organize and discuss various tactics. As a pilot plan, initially, four groups were initially created: IVTT (Chr 5, 10, 15, 16, 19), Cancer (Chr 1, 8, 20, 9, 11, 13, 7, 17), Reproduction (Chr 2, 14, X, Y) and Membrane (Chr 4, 18, 21). At the Vancouver HUPO congress, the IVTT, cancer and membrane proteins cluster teams met for the first time during the breakout session. At the 14th C-HPP workshop in Xiamen, the creation of one more cluster, called the “Neurodegenerative disease group (Chr 1, 3, 6, 11 and 12)” was suggested. Of course, this structure is rather flexible in that one chromosome team can join multiple clusters depending on the specific goals of their projects or temporal need of assistance from other expert teams. Each group would have some consensus on their future activity. It was recommended that any team having a similar target disease or biological questions should share their data and resources to deepen the scientific insight and promote their activity during the 14th C-HPP Xiamen Workshop (May 2016). For example, the cancer cluster collaboration group meeting was held on May 20^th with great participation (>60 people).

Currently, the Chinese (Chr 20) and Korean Team (Chr 11) have now explored such possibilities to share their specialty database (e.g., RNA Seq and MS profiling of SAAVs). As suggested by Gil Omenn in Xiamen, we look for some additional targets for our study in Taipei workshop. For example, cancer stem cells may be good targets for PE2 proteomic analysis due to their heterogeneous nature, which makes easy to find MPs. As such, lnc RNA, Amplicon and SAAVs will also be good targets for cluster group studies. We anticipate that restructuring our C-HPP associated teams with a strong focus on the project will bring streamline in the leadership of each team and logistical strategy on completing the project. It will also be a good chance in getting more efficient research works for clustered teams.

C. Perspectives

This new move will not only stimulate less active teams by giving them an opportunity to identify a new PI as well as additional working members but also make synergistic outputs by working together with other teams across chromosomes under the specific goals (e.g., missing protein validation, data integration, disease mechanism, biological studies using the same resources and technology platform). Regarding more efficient collaboration within HPP group, since C-HPP has a strong technological aspect to improve detection of proteoforms (including missing proteins), we can enhance our collaboration with B/D-HPP teams and CPTAC led by NCI. For instance, if we identify a missing protein or a proteoforms, we can provide the analytical method to study their functionalities. This should define the collaboration with B/D-HPP teams with addition that they can be a source of precious sample collection for the studies of biological/pathological implications of missing proteins, important for both teams. With an informal coalition, more efforts will be put on metrics to unequivocally define those newly detected protein/proteoforms. Further to this, we can build a consensus on identification of cell types, tissues or biological conditions providing the highest probability of detecting a given protein/proteoform. This also brings improved methods and workflows allowing detection and quantification of missing proteins/proteoforms.

*Note: The part of content was taken from Editorials of 2016 JPR Special Issue (Paik et al., 2016).

2. The C-HPP 50 MP Marathon Challenge: Not Missing the End game, by Christopher M. Overall, Co-Chair of C-HP

A. Background and Aims

As missing proteins (MPs) are gradually discovered, attainment of the goal of the HPP is coming ever closer. However, the barely hidden proteins that are close by or in plain sight are likely the first to be found. We expect the law of diminishing returns to dominate more and more in specific MP hunts. Had the HPP been organized differently, we could envision that groups would leave the hard MPs for someone else: what is everybody’s is nobody’s! Hence, the beautiful hidden underlying structure of the C-HPP provides a particularly strong strategy to deal with this challenge. A notable strength of the C-HPP approach is that it breaks down the human proteome into more reasonable bins based on chromosomes. Thus, although most proteomic studies are chromosome agnostic, the data management is not, nor is the responsibility for everyone doing their fair share of the MP work. We strongly feel that the individual chromosome groups will increasingly take on the responsibility of completing the protein list for each chromosome to fill in the last MPs, the ones hardest to find, the ones that no one else will tackle.

B. Approaches

We suggest that group or national pride will soon start to be a driver for the first group to produce a high-accuracy protein part list for their chromosome. As seen in many papers in this issue, several approaches to the search for MPs include less accessible or poorly studied tissues, common tissues but at different developmental stages, stem cells and human mutations that alter pathways that perhaps invoke compensatory paths that use a former low-abundance MP (e.g., an MP once active in development), dedicated SRM and SWATH searches, new technologies and antibody pull out as a few examples. All of these and more can be levered upon RNA Seq analyses of different human tissues to optimize searches for the right tissue and developmental stage, e.g., to increase the probability of revealing a shy MP.

C. Perspectives

Thus, with this being the sixth year since the announcement of the HPP at the Sydney HUPO meeting, with many approaches having now been distilled and circulated and initiatives started, we feel it is now time for the C-HPP as a team to really get serious! Thus, we are challenging each chromosome group to target 50 MPs for discovery this year before the Dublin HUPO! Perhaps these MPs could all be on either the long or short arm of a chromosome to come closer to reaching the goal (completing one arm of a chromosome), or the teams could go for all members of a family of proteins encoded on a chromosome or track their chromosome proteins during fetal or tissue development. In any case, at the C-HPP workshop this year in Taipei, these strategies will have been discussed as a means to really start closing the numbers of MPs found to complete the first draft of the Human Proteome. Get ready, get set, go!
Fig. 2. Perspectives: A possible direction of harmonized collaboration between C-HPP and B/D-HPP (plus Pillars) Initiatives. (from Paik et al., 2014, JPR Editorials, 13, 1-4).

Click here to go the overview of C-HPP activities in HUPO 2016, Taipei.