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As New HUPO Initiatives Take Root, HPPP Researchers Debate Moving On to Disease

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MUNICH, Germany — Even as several HUPO Disease Biomarker Initiatives are being established (see story), researchers involved with the Human Plasma Proteome Project debated this week about whether the second phase of the international plasma project should involve disease research, or whether the consortium should continue to focus on technical issues such as result-reproducibility and standardization of sample processing and data analysis.

During an HPPP workshop session at the Fourth Annual Human Proteome Organization Congress, held here this week, Samir Hanash, a faculty member at the Fred Hutchinson Cancer Research Center and former HUPO president, outlined four possible models for dealing with disease research within the HPPP:



"We must figure out how to move forward."

In the first model, the HPPP would have a number of subgroups that deals with specific types of diseases. For example, there could be a brain disease group that deals with finding proteins related to brain disease within the plasma, and a kidney disease group that finds plasma proteins related to kidney disease.

In the second model, all disease research would be done together by all members of the HPPP.

In the third model, the HPPP would pick one disease to focus on together as a "proof of principle" disease.

In the fourth model, the HPPP would become a virtual project that takes data from other HUPO initiatives, such as the Human Liver Proteome Project or the Human Brain Proteome Project, and concentrates on the bioinformatics of the data so that it can be efficiently accessed and analyzed.

"We must figure out how to move forward," said Hanash.


Pros
Cons
Having the HPPP focus on high-profile diseases could increase awareness for proteomics technologies — which in turn could bring additional funding to the consortium. Basic questions about plasma, such as the variability of plasma proteins within the population, still loom. These questions may be more suitable for an international consortium to address than questions about specific diseases.
"Having an expert panel focus on disease rather than using any single technology to study a disease would be something that people are eager to see."
"Biological variability should be studied before cohort studies."

But rather than discussing how to move forward with disease research, some members of the HPPP questioned whether it is a good idea to have any type of a disease model at all within the HPPP.

Martin McIntosh, a principal investigator in the computational proteomics laboratory at the Fred Hutchinson Cancer Research Center, pointed out that there are basic questions about plasma, such as the variability of plasma proteins within the population, which have yet to be addressed. Those kind of basic questions are more suitable for an international consortium to address than questions about specific diseases, McIntosh said.

"Biological variability should be studied before cohort studies," he said.

Other members of the HPPP consortium suggested that studying what is the normal state of serum and plasma, and studying the differences in plasma proteins between males and females, and young and older people, would be more suitable questions for HPPP to tackle than disease proteomics.

On the other side, Peter Schultz-Knappe, the chief scientific officer of Hannover, Germany-based proteomics company BioVisioN, pointed out that having HPPP focus on high-profile diseases would generate awareness for proteomics technologies, and bring funding to the consortium.

"Having an expert panel focus on disease rather than using any single technology to study a disease would be something that people are eager to see," said Schultz-Knappe.

Catherine Fenselau, a professor in the department of chemistry and biochemistry at the University of Maryland and the president of US-HUPO, agreed that moving on to disease research would make the HPPP more fundable. However, she favored more fundamental studies over clinical studies.

"We're not ready to do actual clinical work. Our methodologies are not ready yet," she said.

Fenselau said that where an international body could really contribute is in database construction, bioinformatics and statistical analysis.

"The HUPO project that has been most consistently funded by international governments is the HUPO Proteomics Standards Initiative," Fenselau said. "That is the only HUPO project that has been given money from multiple governments."

Fenselau added that one option if the HPPP is to study disease is to use mouse models of diseases that have less variation between individuals than humans.

Richard Simpson, a professor at the Ludwig Institute for Cancer Research in Melbourne, Australia, who headed the sample-preparation and -handling committee during the first phase of the HPPP, pointed out that the consortium has still not issued any concrete guidelines for how to best handle plasma and serum samples.

"Although we've addressed a lot of blood collection issues, such as citrate, heparin and EDTA, we still have not addressed storage and time issues, nor collection tubes," he said.

As an example of a sample-handling issue that people should be made aware of, Simpson pointed to a case study that showed that a particular protein, MMP-9, rapidly decreased in activity over a period of three months, despite being stored at -80 C.

"Tissue collection is very expensive, and uses precious patient resource, and we need to address those issues," said Simpson. "What does HUPO recommend in terms of a collection protocol?"

Several other HPPP researchers suggested that the consortium address the issue of protein quantitation as a next step. One suggestion was to take a serum sample and spike it with certain proteins, and to do a study to see if researchers could detect which proteins were spiked.

In his concluding remarks, Gil Omenn, the chair of the HPPP said that it would be quite feasible to have a working group of HUPO laboratories that focus on one or a group of diseases. However, the crux of the debate was whether or not the consortium is ready for disease study.

"What is the reliability of the same sample run twice in the same laboratory, or in different laboratories?" Omenn asked. "Are we ready for disease study?"

— Tien Shun Lee ([email protected])

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