What Is Your Guess?
ANSWERS
1. In the tube on the right, the gel is not between the
cells and plasma. This is a random error that occurs
with unknown frequency.
2. The purported culprit is insufficient centrifugal
force. It is unclear why it occurs when the correct
centrifugal force is used.
3. The results (i.e., for glucose, creatinine, CO2, calcium, urea, sodium, potassium, chloride, protein,
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, magnesium, phosphorus, iron, and transferrin) were the
same as those for a paired tube that had the expected gel migration and no thrombin. Such samples can be used, but they should be treated as
unseparated samples and either used or separated
immediately.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of
data; (b) drafting or revising the article for intellectual content; and
(c) final approval of the published article.
Authors’ Disclosures or Potential Conflicts of Interest: Upon
manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: D.E. Bruns, Clinical Chemistry, AACC.
Consultant or Advisory Role: D.E. Bruns, Roche.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: D.E. Bruns, NIH (grant no. U01-DK-060990), Abbott Laboratories, Siemens, and Partnership for Clean Competition.
Expert Testimony: None declared.
Acknowledgments: BD provided the thrombin-containing bloodcollection tubes.
News & Views
Too Many Roads Not Taken in Biomarker Discovery:
The Story of Missing Tools
Sean A. Agger*
The draft sequence of the human genome was completed in 2000, and scientists, funding agencies, and
industry all claimed at the time that this groundbreaking accomplishment would translate into benefits for
modern medicine by identifying “druggable” protein
targets. Surprisingly, today a majority of the research
remains focused on a small number of proteins that
were identified before the sequencing of the human
genome. The fact that protein research has not changed
despite the “genomic revolution” highlights 3 important questions. First, has the Human Genome Project
produced the “fruits” we thought it would? Second,
why do scientists continue to study the same proteins
Gundersen Lutheran Health Care System, La Crosse, WI.
* Address correspondence to the author at: Gundersen Lutheran Health Care
System, 1900 South Ave., Mail Stop H04-008, La Crosse, WI 54601. Fax
608-775-6666; e-mail [email protected].
Received August 22, 2011; accepted August 25, 2011.
that were identified in the pre– human genome era?
Finally, how can we encourage the study of the novel
proteins that have been revealed as a result of the Human Genome Project?
These questions and some potential solutions are
discussed by Edwards et al. in the commentary “Too
Many Roads Not Taken” (1 ). These authors focused on
research surrounding kinases, nuclear receptors, and
ion channels, all of which are major contributors in the
development of disease and are key targets for drugdiscovery programs. In a bibliometric analysis, Edwards et al. discovered a consistent pattern of research
activity in these protein families over the past 20 years
suggesting that the newly available genomic data have
not substantially influenced biomedical investigation.
Surprisingly, 50 of the protein kinases that were most
commonly referenced before creation of the genome
draft still make up an overwhelming number of the
citations in the postgenomic era. This observation
holds true although ⬎500 kinases have now been anClinical Chemistry 57:11 (2011) 1621
News & Views
notated and hundreds of them have been linked to disease. The story for nuclear receptors is similar, with the
most commonly cited proteins remaining the same
over the last 10 years. In fact, the 6 most cited nuclear
receptors received 71% of the citations in 1999, and the
same 6 receptors continued to garner 72% of the citations in 2009, again highlighting the challenge researchers have had in using the genomic data.
A frequent but false assumption is that previous
research has implicated these highly cited proteins as
being central to disease and that all other proteins have
been shown to be irrelevant. The evidence does not
support this hypothesis. For example, a variety of genetic approaches have demonstrated that ⬎11 protein
kinases are linked to breast cancer, but the majority of
citations in 2009 focused on just a single protein kinase
(CDC2). The same is true for nuclear receptors: A variety of genomic approaches have linked 37 of 48 nuclear receptors to disease, but in 2009 the focus remained on the same 3 nuclear receptors that have
remained the most highly cited since the early 1990s.
Edwards et al. hypothesize that the continued bias
in protein research is due to several factors, perhaps the
most important being the lack of research tools. Interestingly, shifts in protein research are likely to be driven
less by scientific hypothesis and more by the emergence
of novel chemical reagents, such as chemical inhibitors,
antibodies, and recombinant proteins. One remarkable example occurred after the commercial availability of high-quality chemical probes for a subset of
nuclear receptor proteins. This novel tool caused a
dynamic shift in focus from the 37 nuclear receptors
originally linked to disease back in the 1990s down to
just 8 nuclear receptors. From a genetics perspective,
these 8 receptors were no more or less important
than the other 29; however, the sheer availability of
the probe created a selection bias that led to the
abandonment of the other proteins. It is clear that
the availability of protein-specific research tools will
be critical to address the current bias in protein
research.
There are a number of things we can do to take full
advantage of the genomic data and help solve the research bias. It will be essential to direct funding toward
projects focused on developing research tools, much as
the high-energy physics community does. The biological community has traditionally looked down on this
1622 Clinical Chemistry 57:11 (2011)
type of work, but it will be crucial for promoting the
study of novel proteins. Furthermore, we will have to
take this approach with the knowledge that tool development is considered “risky science” and does not have
a high likelihood of success. Many scientists also understand that the current funding and peer-review process is risk averse. Young faculty and graduate students
face a great amount of pressure to generate results
within a short time span, a situation that encourages
the use of previously well-established (and not novel)
systems and continues to reinforce this research bias.
One solution to this problem is to fund innovative and
creative investigators for longer periods of time. That
would encourage more exploration and risk with their
research programs and facilitate the study of new and
uncharacterized proteins.
It is clear that aspects of the current system have
allowed the introduction of substantial bias into our
research on proteins and the genome, although we
have unbiased genetic methods and tools that have
linked many unstudied proteins to disease. Critical
for moving forward will be for the biomedical community to promote the study and characterization of
these contemporary proteins that are now hidden in
plain sight. Such steps will be crucial to take full
advantage of the findings of the Human Genome
Project and to reap the benefits from this remarkable
achievement.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
Reference
1. Edwards AM, Isserlin R, Bader GD, Frye SV, Willson TM, Yu FH. Too many
roads not taken. Nature 2011;470:163–5.
DOI: 10.1373/clinchem.2011.174508