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At HUPO 2019 Proteomics Looks to Solidify Its Place in Broader Research World

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This story has been updated to clarify the organizational structure of the Human Cell Atlas project. 

NEW YORK – Gathering last week in Adelaide, Australia for the annual meeting of the Human Proteome Organization, the proteomics community continued its years-long push towards increased clinical relevance and integration with other omics disciplines.

GenomeWeb did not attend the meeting but spoke with a number of scientists about their impressions of the proceedings.

Of particular interest, said several researchers, were questions around driving wider uptake of the discipline, especially within large government-funded projects that have historically been genomics-focused.

Stanford University professor Michael Snyder, a member of the organization's council, noted that Sudhir Srivastava, chief of the cancer biomarkers research group at the National Cancer Institute, was heading a new initiative aimed at driving interest among funding groups for including proteomics in their research efforts.

"More and more of these initiatives are multiomic, now," Snyder said. "And it's really important [for the proteomics community] to be engaged. There's a lot of interest in making sure proteomics becomes part of these major [National Institute of Health] and NCI efforts."

He cited the example of this issue in the Human Tumor Atlas project, which was announced in 2017 as part of the Cancer Moonshot Project, but which, he noted, includes relatively little in the way of proteomics work.

Mark Baker, professor of proteomics at Macquarie University, likewise said there was considerable discussion at the meeting around "the visibility of proteomics and the Human Proteome Project," with the general consensus being that more effort is needed to "make sure proteomics is engaged as a major player in all of the major initiatives that come out of NIH and NCI and to make sure that we're at the table, so to speak, to show what proteomics can add."

This has long been a challenge for proteomics, despite the existence of major proteomics-focused NCI initiatives like the Clinical Proteomic Tumor Analysis Consortium (CPTAC).

Emma Lundberg, associate professor at Stockholm's KTH Royal Institute of Technology and one of the leaders of the Human Protein Atlas project, which is working to map the subcellular localization of human proteins across a wide variety of tissues, suggested that this is in part due to the technical challenges and limitations — both real and perceived — of proteomics compared to nucleic acid-based technologies.

That gap, however, has closed somewhat in recent years as approaches like data-independent acquisition mass spec and improved isobaric tagging methods have made large-scale, reproducible quantitation feasible at the proteome level. Additionally, advances in single-cell proteomics, both on the antibody-based and mass spec-based side, make proteomics a plausible complement to single cell nucleic acid analyses.

"Mass spectrometry is getting much more sensitive to where we can start to do single-cell proteomics, which will be very powerful," Lundberg said. "And proteomics overall is becoming an established kind of routine measurement that can actually go in the clinic."

"I think, in general, it has become clear that proteomics is a very mature technology that should be used in not only the field of proteomics but should be involved in all areas of science," she said.

She suggested that the field needed to take a more proactive approach to integrating itself into the larger world of life science research.

"I think it's a matter of the proteomics community; we can't just wait to be invited always," she said. "We can address multiomic projects as well by, for instance, including sequencing in our projects."

Her presentation at HUPO made the case implicitly for the need to include protein-level data in biological studies.

"I talked about the cell cycle and how it's regulated and how there's many genes that are known to be cell cycle-regulated, but that we also find many proteins that are cell cycle-regulated — so highly expressed at some points and less expressed at other time points — but which are stable [across the cell cycle] at the RNA level," she said. "And there will always be discrepancies like that."

"If you analyze proteins you are closer to function," she said. "Genomics is super powerful because of the throughput and cost and what you can do with it, but you will get so much more informative data if you also do proteomics."

Lundberg's work with the Human Atlas Project provides an example of proteomics carving out a space for itself within a larger omics initiative. The Human Protein Atlas project is working with the Chan Zuckerberg Initiative on the Human Cell Atlas project, a global initiative supported by organizations including CZI, the Broad Institute, and the European Bioinformatics Institute that aims to create a reference map of all the cells in the human body.

Her suggestion that proteomics researchers incorporate sequencing into their own projects touches on another area of significant focus at the HUPO meeting, the burgeoning field of proteogenomics.

Janne Lehtiö, head of the cancer proteomics mass spectrometry group at the Karolinska Institute and a leading proteogenomics researcher, said that growth in interest in proteogenomics from last year to this year was "striking."

"Last year we had the first proteogenomics session at the HUPO meeting and this year we had the session again, but [this year] you could also see proteogenomics in lots of other topics and sessions," he said. "So, I think this multiomics analysis has really picked up."

Driven by technologies like next-generation sequencing and improvements in the breadth and quality of proteomic data, proteogenomics has seen increasing adoption in recent years. The approach integrates protein and nucleic acid data in the hope that combining multiple levels of molecular information will enable better understanding of biological and disease processes and improve biomarker discovery and development.

Initiatives including CPTAC and the US Department of Defense-led APOLLO program have major proteogenomic components. At the HUPO Meeting, Henry Rodriguez, director of the office of cancer clinical proteomics research at NCI and co-developer of CPTAC and the APOLLO program, provided an overview of the funding mechanisms for another proteogenomic initiative he developed, the International Consortium on Proteogenomics, which he helped launch in 2016.

"I think genomics has been driving [omics research] because genomics has been great at finding disease-related genes," Lehtiö said. "But what genomics has been poor at, relatively speaking, is finding predictive markers for, for instance, selecting patients for therapies. It has been good at target discovery but not that good in the biomarker field. And I think that where proteomics can play a role is to connect the molecular genotype to the phenotype."

Lehtiö and his lab published on their proteogenomic pipeline last year and have since used it for studies on breast cancer identifying new potential cancer neoantigens looking at "how cancer genome aberrations can be converted into novel coding regions and protein variants."

Baker said that he believed the increased emphasis on proteogenomics within proteomic researcher had been part of "a deliberate strategy" to increase the field's exposure within more established areas like genomics, one that he added appeared to be succeeding.

The HUPO meeting also occasioned updates of various organization initiatives, including Snyder's Human Personal Omics Profiling (hPOP) Project, through which he aims to collect proteomic and other data on meeting attendees each year. He enrolled 106 participants at the 2016 meeting, 115 at the 2017 meeting, and 90 at the 2018 meeting.

He said the project has recently obtained data from lipidomic profiling of these participants and has observed shifts in participant profiles based on the location where they were sampled, presumably reflecting responses to the different environments.

"For people who did multiple samples, the Taipei samples [from 2016] are looking different from the other samples [collected in Dublin in 2017 and Orlando in 2018], suggesting that there is an environmental effect," he said. "We don't know the meaning of that yet. It could be the food, it could be anything. But [the shift] looks pretty clear."

Meanwhile, the organization's flagship project, the Human Proteome Project (HPP), which aims to identify a protein product from every protein-coding gene in the human genome, continues to chase down its targets, though the effort has reached a stage where the remaining proteins outstanding could prove particularly difficult to find, said project chair Gilbert Omenn, professor of human genetics at the University of Michigan.

There are number of reasons proteins might go undetected, Omenn noted. For instance, some might be expressed only under very specific conditions that are difficult to capture. Others might be embedded in membranes and be difficult to solubilize. Still others might not have the lysine and arginine residues required for the trypic digestion commonly used in proteomic workflows.

Nonetheless, the group is closing in on identifying proteins to 90 percent of the predicting protein-coding genes, Omenn said, predicting it would hit that threshold in the next year.

In a paper published in August in the Journal of Proteome Research, scientists including Omenn detailed the current state of the effort, observing that the project has identified 17,694 proteins with the most stringent level of evidence, representing 89 percent of the 19,823 predicting coding genes. That figures was up from 17,470 the year before and up from 13,975 in 2012.

Looking ahead, Baker, who is also one of the leaders of the HPP, said that the effort will work to define itself in terms of looking more closely at the proteins' biological functions in health ad disease. The project will mark its 10-year anniversary at next year's meeting in Stockholm, and Baker said organizers are "assembling a decadal report to let people know where we are at and to clearly define the way forward for the next decade."

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