If there was a single word that defined the proteomics world in 2003, it would have to be ‘biomarker.’ Nearly all of the 11 leading researchers interviewed for this issue named biomarkers, and in particular their application to pattern-based clinical diagnostics and toxicology, as one of the most memorable developments of 2003 — and pointed to 2004 as a defining year for determining whether the trend will continue to boom, or whether it will bust.
“Have you actually talked to someone who is not working on biomarkers?” Bill Hancock, professor of chemistry at the Barnett Institute at Northeastern University, joked when asked whether he was involved in the new trend. Indeed, it is hard to find a researcher or company who didn’t at least dabble with the idea in 2003, although most are not yet sold. “I think it’s a healthy blend of excitement and skepticism. You don’t want to see everything too dark, but can’t say it’s wrapped up either,” said Paul Tempst, director of the protein center at Memorial Sloan-Kettering Cancer Center.
Emanuel Petricoin, whose NCI-FDA team originated the pattern-based biomarker concept in 2002, was less shy about the technology’s potential, which he said “really nucleated, crystallized in 2003.” According to Petricoin, “There are not a lot of smoking-gun examples where proteomics is having an immediate clinical impact, and this is one that people are hanging their hats on and saying ‘here’s an example where right now, there’s an unmet need being filled.’”
Richard Caprioli, who published a paper in August on non-small-cell lung cancer biomarker patterns, said that much validation still needed to be done, but that 2003 showed convincing proof-of-concept that pattern-based biomarkers could work. “If we can find molecular markers for the disease and the aggressiveness of the disease, then that would be a magnificent goal,” Caprioli said. “What I think this last year has shown is that in fact this appears to be at least to some extent what we’re finding.”
The Big Exam in 2004
Still, even Petricoin and Caprioli, admittedly two of proteomics-based biomarkers’ biggest cheerleaders, stressed that 2004 will be a critical year for validating whether preliminary findings hold up. There are many questions still to be answered, researchers said, the most immediate being whether pattern-based biomarkers can be shown to be reproducible. “This coming year, I think the trend will be to really understand how reproducible these platforms are, and try to get a sense of within and between laboratory reproducibility — that’s what we need to focus on,” Petricoin said.
Beyond reproducibility, however, there are a host of other unresolved issues. “I believe in 2004, people will really need to pay attention to what are the best controls for a new biomarker discovery,” Denis Hochstrasser, president of the scientific advisory board for GeneProt and chairman of the department of clinical pathology at Geneva University Hospital, said. “People need to realize that patients do not go to a hospital if they are not sick, so the control population should not be healthy people — they should be sick people with another disease,” Hochstrasser said. He pointed to the example of a patient with a heart attack who might display a biomarker pattern indicative of inflammation, a condition that accompanies a large variety of diseases and thus one that would not be a useful pattern for diagnosis.
Ruedi Aebersold, inventor of ICAT technology and co-founder of the Institute for Systems Biology, felt that the proteins that make up biomarker patterns need to be identified and quantitatively described before they can be considered credible. “I quite firmly believe that one needs to know what someone is measuring,” he said. But Caprioli said that while identification was an eventual necessity in his view, “along the way we can help the clinician treat patients … even if at that point in time we don’t fully understand the molecular basis of the disease.”
Aebersold also suggested that researchers should take a step back to animal models before jumping right into clinical trials. He pointed to work he has undertaken with a number of other groups in collaboration with the Fred Hutchinson Cancer Research Center in Seattle to look for proteomic patterns in a controlled mouse model. The mice the groups are using are inbred, age- and sex-matched, so that the only variable is disease. “I hope that [next year] this will happen in a broader sense that these techniques are benchmarked in a controlled experiment as opposed to everybody just grabbing sera from patients which are usually very poorly documented,” he said.
Hancock added that some sort of ranking system for biomarkers should be put in place in 2004. “So we’re using biomarkers for some diagnostic or monitoring clinical trials, and we’ve got 100 — how do we pick the top 5?” he said.
Additionally, the application of existing methods to more and more diseases should also be an important focus for 2004, Caprioli added. “What certainly is going to happen is that we’re going to apply it much more vigorously and to try now to find out to what extent preliminary studies can be extrapolated to a general case,” Caprioli said. “Will all diseases show these kinds of molecular fleets of markers, or are they just some? … My guess is that it will be generally applicable.”
While there are clearly many potential focuses for biomarker research in 2004, most important, Petricoin said, is to be rigorous and to “not allow the enthusiasm for the potential to blind you to the methodical plodding along of all the components.” Otherwise, the danger is that 2004 could be the year that biomarkers bombed. “The thing that would be the killer would be [that] people are excited and intrigued and enthusiastic about taking these proteomic tools and employ[ing] them at the bedside. But just like gene therapy, if you have a few early failures, the entire field could collapse around itself,” Petricoin said. The last thing you want researchers in the future to say, he said, is “‘Oh, you remember when proteomics was going to be the next greatest thing and it turned out to not be anything?’”