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Are Proteomic Tools Too Costly and Time-, Labor-Intensive for the Clinic?

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SAN DIEGO — Until instruments used for proteomics research become cheaper and more user-friendly, proteomics may always play second fiddle to genomic technologies in the clinical setting, according to participants in a panel discussion at the annual meeting of the US Human Proteome Organization, held here this week.

One panelist, Patrick Brown, a professor of biochemistry at the Stanford University School of Medicine, said to date the cost of instruments such as mass spectrometers, and the special training needed to run them, have meant that proteomics has poorly served the medical field, and, as a result, the discipline has become marginalized compared to genomics.

Brown, who has worked extensively with DNA microarrays, made his remarks during a panel discussion originally meant to the address the challenges facing proteogenomics. But as none of the panelists could define proteogenomics, the conversation instead turned into an evaluation of proteomics, its highs and lows, and what kind of future may be laying ahead for the field.

Another panelist, Ruedi Aebersold, a professor of systems biology at the Swiss Federal Institute of Technology, was critical of the direction some research has taken, and decried what he said was the science's lack of clear objectives.

A fundamental problem, Aebersold said, is that proteomics continues to "operate in a perpetual-discovery mode" when a more targeted approach would provide greater benefits.

"If we continue in this perpetual discovery mode, the high-performance application of the [the tools] will remain in specialized labs," and the potential impact of proteomics will be lost, he said.

The field also needs to better define the issues it wants to address, including narrowing down what the discipline wants to achieve and how it will do it, he said. According to Aebersold, proteomics "has to define achievable goals," such as creating a basic human proteome map in which one protein would be mapped for every gene, an approach that HUPO first threw out last year when it proposed the Human Proteome Project.

A third panelist, Michael Snyder, director of the Yale Center of Genomics and Proteomics, added that proteomics is missing "basic elements," including the C-terminus and N-terminus of all proteins.

On the Couch

It is not the first time those working in proteomics have stopped for a self-evaluation, and in the past, similar discussions have taken on the look and feel of a therapy session in which the patient tries to figure out where his life went wrong.

This week, the panelists and some audience members, mindful of the criticism and financial challenges the discipline has had to weather in recent years, were quick to point out the progress that it has made.

Several panelists said that one of the key accomplishments of proteomics has been the delineation of complex biological components and organisms, which have in turn led to insight into diseases.

For his part, Aebersold said a sometimes-overlooked benefit of proteomics has been its success in developing tools and instruments that address questions about biomarkers while also shedding light on more basic biological mechanisms and processes such as interaction networks and signaling pathways.

"So I don't think we can underestimate the degree to which proteomics has driven that part of science," said Aebersold.

And Gil Omenn, a professor of internal medicine, human genetics, and public health at the University Michigan, cited the "unbelievable" development of mass-spec technology, such as MSn and electron-transfer dissociation.

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But the discipline has a good deal of work ahead of it before it can elbow its way into the clinic — or before other tools elbow it out of its own field. For instance, Stanford's Brown suggested that despite their advances in recent years, mass specs may be holding the field back, especially in translating the science to the clinic, because of the special skills needed to operate them.

"I'm not sure why that is, but it wouldn't have to be the case [that] these tools are so specialized," he said.

He also said that the power of the mass spec may have been over-sold, and that it may continue to be over-sold, and that "the reality" of what can be done with the instruments "has fallen short of the theoretical capabilities."

Aebersold agreed, saying that neither proteomics in general nor the technology in particular had reached the level of maturity that would be required for the discipline to enter the clinic. Trying to push the science into the clinic prematurely, he added, "may do a disservice to the field."

Beside the cost of the equipment, Brown said the "biggest shortcoming" of proteomics has been biomarker discovery, in particular the way in which hype from a few years ago and the consequent failure to live up to it "unfairly damaged the proteomics community at large."

He also said that the field, unlike genomics, has had an "extreme neglect" of variations: Whereas genomics has focused on genetic differences and their possible meanings, the proteomics field has not focused on those areas, which has contributed to the science's comparatively smaller role in the clinic.

However, an audience member pointed out that while DNA-based tests are a recent addition to the clinic, protein assays, such as those used for pregnancy tests, have been around for a much longer time, an indication that proteomics has had some clinical utility.

But Brown questioned if such tests can be counted as proteomics success stories since "I don't think they are proteomics anymore than PCR tests are genomics."

And as for Aebersold's idea of a human proteome map, Brown said that even if one existed, "how would you make this useful to biologists?"

In response, Aebersold said such a map could enable large-scale quantitative analyses that could lead to the development of assays and other tools. Yet according to Brown, the state of the technology combined with the time, cost, sample-prep requirements, and specialized knowledge needed for those ends would prevent them from becoming routine — a prerequisite for clinical uptake.

Rather than investing in a human proteome map, Brown said that creating a map of individual tissues, organs, or fluids may serve a greater purpose at this point, even if it were a low-resolution, preliminary map.

Finally, asked about the future for proteomics other than need for cheaper and easier-to-use tools, panelists said they would like to be able to observe what is happening in a single cell and see more work in quantitation and expression in different organs.

According to William Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, considering the ongoing trajectory of healthcare costs, tools that can "help allocate care in a way that will be more efficient financially" should be a focus for development.

For example, he said, a proteomics-based tool that can tell a clinician which patient needs colorectal surgery — an expensive, invasive, and risky option for a variety of diseases — would serve a clinical need.

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