Biomarker Verification Is Critical
Leigh Anderson, Ph.D., founder and CEO of the Plasma Proteome Institute (www.plasmaproteome.org), explains that the bottleneck happens when there is no feasible way to analyze 1,500–2,000 samples. “If you were to ask how many people have ever analyzed that many samples, the answer would be nobody,” says Dr. Anderson. “You can’t do it with the current discovery platforms; you need alternative technologies. It’s a difficult problem, and there is a lot of enthusiasm in the community to expand the technology portfolio to solve the problem.”
The shortfall in new protein clinical diagnostics emerging from proteomics research appears to reflect a lack of critical biomarker verification capacity rather than a failure in biomarker discovery, in which large numbers of candidates are routinely uncovered, notes Dr. Anderson. “The primary problem is that over 95 percent of these candidates fail as reliable disease-specific indicators in the general population, where biological noise often overpowers the weak biomarker signal.”
Dr. Anderson says that one way to approach the bottleneck is to place primary emphasis on development of technology and collection of sample sets specifically tailored to support statistically definitive tests of large panels of biomarker candidates. “There are two ways to solve the bottleneck. One is to miniaturize immunoassays, which is what the array people do, and it’s a very interesting technical approach, though limited by cost and assay quality issues,” notes Dr. Anderson.
“The other way is quantitative mass spectrometry. Of course sensitivity is an issue with the MS approach, so what we’ve done is create a hybrid with immunoassay sensitivity and mass spectrometry specificity, a method called SISCAPA.”
This approach incorporates many MS tools (e.g., MRM) that have been around for at least five years for measuring drugs and metabolites, according to Dr. Anderson. The novelty, however, is in combining MS with immuno-enrichment and applying the combination to peptides and proteins. “It’s a great way to get an accurate measurement of a series of specific targets,” Dr. Anderson explains.
The key thing, Dr. Anderson says, is that an argument for a streamlining of the validation process is needed. “It has been challenging to get people on board because discovery has been perceived as more fun and higher leverage, but more people are getting smarter about it, especially once they see that biomarker candidates don’t advance themselves to the clinic.”
While some bemoan that technology is not keeping pace with discovery, there’s lively discussion that suggests the opposite is true. Dr. J. Hunter, in addition to chairing the proceedings, will also be presenting recent proof-of-concept studies Caprion has done. “One of the biggest challenges I see is not the technology itself but the uses of that technology,” says Dr. J. Hunter. “The technology is capable of answering the questions we ask, but it’s a matter of overcoming the perception that it’s not.”