AMSTERDAM, the Netherlands — As the Human Proteome Organization evaluates the feasibility of mapping the entire human proteome, it could face significant headwinds from funding agencies, according to officials presenting at the annual HUPO conference.
At HUPO’s annual conference, held here this week, the organization talked about plans for its long-discussed Human Proteome Project, a $1 billion effort to provide a reference map of the human proteome. But during sessions held the weekend before the conference officially kicked off, word from funding agencies from various nations was that the project may find it difficult raising cash.
While every agency represented at the session said that it is interested in the project, they expressed concerns about the scope of the project, the benefits of such a project to the scientific community, and how such a large-scale project would be organized and controlled.
Colja Laane, director of the Netherlands Genomics Initiative, said that the agency is “definitely interested in participating in such an initiative,” but such a project would make sense only if it would provide not only knowledge about proteins, but if it also were to expand the knowledge base of life sciences broadly. Several other funding agency representatives reiterated the point.
Laane added that the $1 billion cost estimated by HUPO to complete the project “is too much.”
Pierre Meulien, chief scientific officer of Genome British Columbia, said that in order for the project to attract funding, HPP organizers will have to tell funding agencies what scientific barriers HPP will bring down. “What's the sea-change, what's the step forward” for protein researchers and also for the clinical community, patients, and other parties, he said.
The most skeptical outlook came from Sudhir Srivastava, chief of the cancer biomarkers research group, division of cancer prevention at the National Cancer Institute, who pointed out two potential roadblocks that could prevent the NIH from backing HPP: the lack of standards in proteomics and budget constraints at the agency.
While the field and HUPO are in the process of developing technology and devising reporting and research standards, the fact that the field still largely lacks them will hurt the chances for NIH funding for HPP. “Funders will ask, 'If there are no standards, why are we doing this?'” he said.
Further, it is no secret that the past few years have been lean ones for researchers seeking NIH money, and the trend is likely to continue into the foreseeable future. According to Srivastava, essentially flat funding to the NIH has led to cuts in existing programs, and during the next few years, new projects, especially large-scale ones such as HPP, will face even more hurdles.
“It's bad timing,” he told HUPO members and audience members.
After the dust settled, Matthias Uhlen, leader of the Human Protein Atlas, said, “What we've learned from funders ... is that they are not ready to go in and launch a proteome project.”
Protein Pro Tempore
Announced in the spring, HPP is a 10-year, $1 billion initiative to map the entire human proteome. Focusing on three technologies — mass spectrometry, antibodies, and protein interactions — the project could be finished within five years assuming the rapid development of new technologies, John Bergeron, immediate past president of HUPO, and a professor of anatomy and cell biology at McGill University, told ProteoMonitor in April [See PM 05/01/08].
The first phase of the project would gather all the “high-quality” proteomics-related mass-spec data to evaluate the ability of the discipline to match mass spectra to the protein-coding genes of the human genome, Bergeron said at the time.
From there, a pilot project would be started to map the protein-encoding genes of human chromosome 21, which at about 47 million nucleotides is the smallest in the genome. To keep HPP manageable, the goal is to determine one “representative“ protein for each protein-coding gene rather than map out every single protein with all its post-translational modifications and isoforms. However, researchers and officials during the meeting here said that the possibility of including post-translational modifications to some extent is up for discussion.
“What we've learned from funders ... is that they are not ready to go in and launch a proteome project.”
In South Korea, a project similar to the one proposed for chromosome 21 has already been proposed. Its aim will be to use mass spectrometry and antibody-based technologies to map the protein-encoding genes of chromosome 13, the second-smallest in the genome. While the Korean government has expressed interest in the project, it has not promised any money yet, said Young-Ki Paik, the president-elect of HUPO.
During the meeting, at an HPP session focused on the scientific parameters of the project, HUPO members outlined some possible end-points to, and deliverables of, the project, including characterizing all major isoforms and splice variants; distributing proteins of at least one representative protein for every human gene; and defining all major protein complexes.
According to Uhlen, short-term deliverables include a public database of validated antigens and antibodies; validated antibodies to the majority of human proteins to be carried out in four projects aimed at chromosome 21; the SH2 protein domain; kinases; and candidate genes for cancer biomarkers.
Longer-term deliverables include the provision of therapeutic targets and disease biomarkers; expression levels of all proteins in body fluids; an expression index of all proteins in cells; and all major splice variants and major proteolytic products.
Several speakers and audience members referenced the Human Genome Project and the lessons that HPP could learn from that effort. Ruedi Aebersold, one of the founders of the Institute for Systems Biology, said that the genome project has demonstrated that a high-quality map is essential to science and can be transformative. Rolf Apweiler, current president of HUPO, said that before the HGP, it would take researchers a few years to find a few genes. The promise of HGP was that it would save time, money, and effort by providing a reference map to gene researchers. And it has, he told the audience.
And while proteomics has been criticized for failing to deliver on a decade-old promise to foment radical changes in medicine, Bergeron said last week that proteomic research has resulted in discoveries “that have changed biology.” He cited yeast research performed by Michael Snyder at Yale University that has shed new light on the function of proteins.
Indeed, some speakers, including Snyder, said that rather than specific end-points and deliverables, which may be attractive to funders, the success of a project such as HPP should be measured in ways that may not be tangible.
Even if HPP is not able to map the entire human proteome within 10 years, “if we can help the scientific community be 10 times better” in carrying out their research than it is now then the project “will be a success,” Snyder said.
Where’s the Value?
But several speakers also noted that researchers, funders, and other participants may resist the project because of proteomics’ lack of results.
“There hasn't been much value delivered to the basic science community and almost no value to the medical community,” said Tommy Nilsson, co-chair of HUPO’s Mouse Models Initiative. Nilsson, who is also scientific manager at the Center for Cellular Imaging and Center for Proteomics at the Sahlgrenska Academy at the University of Gothenburg, cited several studies in which only a small percentage of participants were able to identify proteins.
For example, a study completed last year by HUPO found that only six of 24 labs successfully identified all 20 equimolar proteins in a protein standard mixture [See PM 09/06/07 and 10/11/07], he said.
While he said he supports HPP, Nilsson nonetheless said that proteomics may still need to prove it can deliver results with smaller-scale projects before it tackles one on the scale of HPP.
Even if such a project were to proceed, many other questions abound: What would HUPO’s role be? Who would do the work — everyone who wanted to participate or only a small cluster of laboratories? Would HPP be directed at a “normal” proteome or a disease-specific proteome? And if so, which disease?
Those and other specifics still need to be sorted out, though HUPO officials said that the organization will not be responsible for governing the project. This week, however, the emphasis was on rounding up support for the effort. Yale’s Snyder, who is also immediate past-president of US HUPO, said that it is important to remember that one reason that HGP was able to proceed and succeed was that it had strong government support in the person of Francis Collins, who was crucial in driving it. Collins had been the director of the National Human Genome Research Institute for 15 years before stepping down in June.
For HPP to be possible, therefore, there will need to be similar support from funders, he said. “You can’t believe in this just because I’m telling you to believe in it. You have to believe in it,” he said. Ultimately, HPP will have to be a collaboration between the research community and the government, but “quite frankly, it’s going to take someone from a very high level [within the federal government] driving this,” Snyder said.