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Fred Hutchinson Researcher Says Correlating Proteome Changes in Disease Trials Can t Wait

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BEIJING — While leaders of various Human Proteome Organization initiatives struggled to standardize techniques during pilot phase studies, Lee Hartwell, the first key note speaker at the HUPO conference, held here this week, urged researchers not to wait until other matters are settled to begin correlating proteome changes with disease and health research.

“As a kid, I always used to eat dessert first, and I’m going to start there now,” said Hartwell, the director of the Fred Hutchinson Cancer Research Center in Seattle. “I’m the director of a cancer center. How are we going to cure this disease?

“We should start now in developing biomarkers for disease and health, instead of waiting until the last step, which is where the goal is listed in some of the HUPO initiatives.”

Hartwell, who won the Nobel Prize for physiology or medicine in 2001, showed that over the past 40 years, there has been virtually no improvement in cancer survival rate, though there has been marked improvement in survival for heart disease and stroke. In general, 40 percent of people who get cancer will die of the disease, Hartwell said.

If cancer survival rate is looked at as a function of the stage at which it is diagnosed, however, it can be seen that early-stage cancer is as curable now as it had been 40 years ago.

“It’s not that we need a cure for cancer. It’s that we need to apply the cure that we have to more patients,” said Hartwell.

Proteomics is a systematic approach that can find biomarkers for the early diagnosis of cancer, Hartwell said. In fact, it is a much more effective approach than drug discovery in terms of both cost and medical results.

“Diagnostics are a very different science than drug discovery,” Hartwell said. “With drugs, you start with a wide pipeline and you end up with one compound, and each step is more and more expensive to develop. With diagnostics, once you get the molecules into the pipeline, you can multiplex during validation.”

While one new drug typically costs $800 million to develop, Hartwell estimated that early-detection biomarkers only cost about $6 million for 60 biomarkers, or about $100,000 per biomarker.

In addition, in terms of therapeutic response, early detection can be much more effective than treating a disease at a later stage with drugs.

“Most drugs don’t cure cancer. They may prolong life for a few months,” said Hartwell. “I think we’re grossly overemphasizing drug discovery medicine in comparison to molecular diagnostics.”

One of the obstacles to developing biomarkers is a limitation in reagents such as antibodies, isotopically labeled peptides, and ICAT, said Hartwell.

The HUPO Antibody Initiative, or HAI, is one Initiative that is trying to deal with the lack of reagents.

HAI members met for the first time during a workshop on Oct. 23. During the workshop, HAI scientists came up with five-year and 10-year plans to systematically generate antibodies against every non-redundant protein in the human proteome.

Mathias Uhlen, the head of HAI who is a professor at the Albanova University Center in Stockholm, Sweden, estimated that there are over 100,000 protein variants in the human proteome. Of those, 22,287 are non-redundant proteins that map to different gene loci.

“Our goal is to generate a uniform antibody collection against every human protein in a non-redundant set,” said Uhlen.

Antibodies are indispensable in that they allow researchers to pull down their favorite protein and study it, said Uhlen.

“They are useful in so many different types of assays,” he said.

The goal for the next five years is to generate at least one validated antibody against 80 percent of the human proteome, said Uhlen. This can be accomplished if 25 new antibodies are generated per week.

Over the next 10 years, the goal is to generate at least two validated antibodies to all proteins in the human proteome, Uhlen said. Priority in generating antibodies will be given to those proteins that are relevant to the other HUPO initiatives, such as the HUPO Plasma Proteome Project, the HUPO Liver Proteome Project, the HUPO Brain Proteome Project and the HUPO Glycoproteome Project.

Another HUPO initiative that will be useful in developing and validating diagnostic biomarkers is the HUPO Mouse and Rat Proteome Project. The aim of the pilot-phase of the HMRP is to characterize and localize proteins in normal and diseased mouse and rat livers, said John Bergeron, the head of the HMRP and a professor in the department of physiology at McGill University in Montreal, Canada. Diseased mice are afflicted with hepatitis or hepatitis carcinoma.

“We have such wonderful rodent models of human disease,” said Bergeron. “If we can match their proteins to the appropriate proteins in humans, it could make for diagnostic tests.”

In terms of HUPO projects that study tissue, many followed HPPP in setting forth initial goals for pilot phase projects.

According to Gilbert Omenn, the head of HPPP who is a professor at the University of Michigan in Ann Arbor, the initial goals of HPPP were to compare the advantages and limitations of various technologies in terms of sensitivity of detection, confidence of identification, ease of operations and costs; to clarify the influence of various technical variables; to decide whether the most abundant proteins should be depleted from serum or plasma; to develop a database for results; and, lastly, to lay the groundwork for large scale studies of plasma and serum biomarkers, he said.

Hartwell urged researchers to start now in developing studies for biomarkers, instead of waiting until the fifth goal.

— TSL

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