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At HUPO 2012, Researchers Look to Prove, Promote Proteomics as Broad Life Sciences Research Tool

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The question of proteomics' place in the larger world of life science research drove discussion this week at the Human Proteome Organization's 11th annual meeting in Boston as researchers gathered to report on the field's progression and potential as well as the obstacles that continue to limit its adoption by non-experts.

Swiss Federal Institute of Technology Zurich researcher Ruedi Aebersold summed up the meeting's overarching concerns during a presentation in which he compared the broad adoption of genomics throughout the life sciences with proteomics' relatively low level of penetration, noting that while advanced techniques like high-end mass spectrometry and protein arrays are now commonplace within proteomics circles, the vast majority of biologists still rely on simple antibody-based methods like western blots for protein research.

Citing a paper by University of Toronto researcher Aled Edwards demonstrating that scientists remain significantly more likely to research proteins for which there are quality antibodies, Aebersold suggested that the ultimate goal of HUPO's Human Proteome Project should be to provide the larger scientific community with "assays to quantify any human protein and the associated software tools and knowledge base to help people implement these assays."

Such talk of proteomics' ability to provide a fundamental base of knowledge for biological research also figured heavily at this week's launch meeting for HUPO's Chromosome-Centric Human Proteome Project, or C-HPP, which has emerged as one of the organization's key initiatives.

First proposed at the 2010 HUPO meeting (PM 2/18/2011) and further fleshed out last year (PM 9/9/2011), the C-HPP formally launched this week, with a number of figures from industry, government, and academia affirming their support of the project, which calls for participating countries to take one of the human chromosomes and characterize one representative protein for each gene located on the chromosome.

The initiative has now assigned out all 24 human chromosomes as well as the mitochondrial chromosome to research groups around the globe, with work underway in a number of countries.

At last year's HUPO meeting, a number of C-HPP teams raised financial concerns, noting that the project's lack of a particular disease or biological focus had in some cases made it difficult to obtain funding.

This question featured less prominently this year as speakers emphasized instead the project's potential as a research tool along with the daunting complexity of the task.

Led by Young-Ki Paik, director of the Yonsei Proteome Research Center in Seoul, Korea; Bill Hancock, chair in bioanalytical chemistry at Northeastern University and editor of the Journal of Proteome Research; and Gyorgy Marko-Varga, a Lund University professor and AstraZeneca principal scientist, the C-HPP initiative consists of two phases.

The first, which is slated to run through 2018, will focus primarily on mapping and characterizing the roughly 6,000 proteins yet to be detected via mass spec, as well as post-translational modifications, alternative splicing transcripts, and non-synonymous SNPs of the roughly 14,300 well-characterized proteins. The second phase, which is planned to run from 2018 to 2022, will focus primarily on validating data from the first phase along with functional studies and developing drug targets and biomarker candidates.

The project calls for each chromosome team to publish at least one paper per year on their work, with this year's papers going to JPR.

At the launch meeting, Sudhir Srivastava, head of the Cancer Biomarkers Research Group in the National Cancer Institute's Early Detection Research Network, applauded the two-phase approach, noting that it would give the organizers an opportunity to shift direction in response to issues that emerge in the initial phase.

Noting the he was "the end user for this project," Srivastava warned that the logistics of the initiative would prove a "big challenge" but that it promises "a number of opportunities for biomarker research."

Hanno Langen, head of exploratory biomarkers at Roche, similarly voiced his hopes for the project, noting the growing importance of proteins in pharma research • both as targets and agents.

"I think this project can deliver great advancement in disease understanding," he said. "That is where I see the greatest value. To understand the interactions of proteins, how they signal… knowing all the proteins, including the proteins we have no evidence of by mass spectrometry, could be a key aspect of understanding disease."

Andreas Huhmer, proteomics marketing director for life sciences mass spectrometry at Thermo Fisher Scientific, told ProteoMonitor that the project appears promising on three counts: it is feasible based on current technologies; it has a clear end-point; and it has the necessary scale.

He noted, though, that the size of the project raises organizational concerns.

"If you compare it to the Human Genome Project, which was driven by a lot more funding, there were a lot of very experienced people who knew how to run very large-scale projects," he said. "And I'm a little concerned that this project won't have that [level of experience]. The individual [chromosome] groups will have their research projects ongoing, but are they going to do them in a way that will be useful to create the resource that we all need?"

Huhmer also suggested that it was important for HUPO and the HPP • which, aside from the C-HPP, has a number of other projects around various organs and disease areas • to find a single focus.

"I think that it's most important for the C-HPP project and HUPO that we create one project; we do it; and we deliver," he said. "We can define many different projects and there are many other HPP projects going on and they are all worth doing, but I think it is important that HUPO creates one project and delivers it in a specific amount of time. I think it is extremely important for HUPO and its mission to demonstrate that we can actually do a project and deliver."

Given the large number of HPP projects going on underneath the organization's umbrella, such a focus seems unlikely. However, Paik told ProteoMonitor, the expectation is that the various projects will over time converge, as the C-HPP's protein mapping and characterization efforts offer new insights for the disease- and biology-driven initiatives.

University of Geneva researcher Jean-Charles Sanchez, who is leading the diabetes section of HUPO's Biology/Disease-Driven Human Proteome Project, or B/D-HPP, agreed, telling ProteoMonitor that the two projects were "totally complementary."

He cited the research of the C-HPP's Spanish team led by Spanish National Center for Biotechnology researcher Juan Pablo Albar, which is tackling chromosome 16.

"They want to [map the proteins] for chromosome 16, but … they are [also] looking at what are the main diseases coming out of this chromosome," he said. "They know it is not only that chromosome [contributing to a given disease], but just looking at the density [of the disease-related proteins] they come out with cardiovascular disease, obesity, cancer] So they really want to relate the chromosome to diseases, and I think that is the next step in HUPO • to really correlate the chromosome and disease together and have tight sharing of information at different levels."

"I'm sure that we will do something with the Spanish chromosome project and diabetes," he added.

Beyond integrating the C-HPP data with other HPP initiatives, the group also aims to place it in the context of other 'omics data, Hancock told ProteoMonitor. In particular, he said, he and Paik have been asked to write a review on the possible linkage of the massive Encyclopedia of DNA Elements, or ENCODE, effort with the C-HPP.

In the case of the C-HPP, "when you're observing a protein, you're not just observing the spectral counts or whatever, you're also aware of the genomic landscape around that particular gene," Hancock said. "Now with the C-HPP, you can say, 'Oh, this region [of a chromosome] has been silenced … and then you can feed that back into the molecular biologists."

Regarding the project's organizational challenges, Hancock cited its informatics infrastructure as the key to maintaining cohesion among the 25 global research groups.

"You try to control the experimentation, but with 25 groups around the world you can't standardize it," he said, noting also that the rapid pace of proteomics tool development further complicates this effort.

"But it's at the end that it gets unified" by the project's informatics process, he noted.

All C-HPP data must be deposited in the Trans-Proteomic Pipeline • a series of informatics tools for processing proteomics data. From there it will be picked up by both the Institute of Systems Biology's PeptideAtlas and the Global Proteome Machine Database run by University of British Columbia researcher Ron Beavis.

There, the data is tested for quality and sorted into chromosomes, Hancock said. "So, for example, if I want an update on chromosome 17, I'll go to those two sites and I'll have the list."

The C-HPP researchers "have a mountain of work in front of [them]," Henry Rodriguez, director of NCI's Clinical Proteomic Technologies for Cancer initiative, said at the launch meeting. "But I think that with the right leadership this is something that will definitely pay off for the scientific community at large."

In a presentation at the meeting's close, Fred Hutchinson Cancer Institute researcher Samir Hanash offered a glimpse of how proteomics is currently making its impact felt in the larger life sciences space.

Hanash is in the process of moving his research to MD Anderson Cancer Center, where he will be joining the McCombs Institute for the Early Detection and Treatment of Cancer in addition to maintaining his lab at Fred Hutchinson.

At MD Anderson he will embarking on a "very ambitious program" investigating early detection of cancer, molecular classification of tumors, and methods of tracking response to treatment.

"We're going to be looking at human tissues, at plasma, looking very intensely at mouse models of cancer, fresh tumor cells… and cancer cell lines… and doing every conceivable 'omics we can do," Hanash said.

"And what is somewhat unique about this picture at MD Anderson is that there is going to be a very heavy investment in proteomics," he added. "And we could only do that [if we had] the notion that we could do a very good job with proteomics. So for that we will need a very good in-depth quantitative [proteomics] analysis that will be as comprehensive and complete as possible."

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