Systems
Biology and Systems Medicine Think of an organism as layered systems of dynamic networks. Two, for example, are the network of signal transduction proteins, and the network of transcription factors turning genes on and off. Both integrate and modulate the information they receive and transmit. To understand how any system is more than the sum of its parts, it is necessary to study it as a whole: "You could study neurons for 50 years and never get a clue that anything like 'consciousness' existed". Three
defining features of systems biology are: Finding Biomarkers A
significant innovation in Dr. Hood’s method
is to first select potential markers that are specific
to an organ of interest that may serve as state-reporter
for the organ, then look for up- and down-regulation
among this set. For example, he found about 300
transcripts that were only expressed in the prostate,
and a subset of these showed differences between
cell lines representative of early- and late- stage
prostate cancer. An antibody was made against one
of these, and used to compare its levels in sera
of early and late-stage prostate cancer patients,
and control patients. Out of 10 patients in each
group, the new marker was seen in 5 each of the
PC patients, and none of the controls. For comparison,
PSA was seen in 0 control, 0 early-stage, and 7
late-stage PC patients. The combination of the two
markers had better selectivity and specificity than
either alone, and clearly more would be better.
Systems Medicine: the Nanolab Dr. Hood’s vision is to characterize 10 - 50 of these organ-specific “state-reporters” for each of 56 organ systems, then to establish a standard test for the resulting 500 - 2500 serum biomarkers. Promising results were shown towards a microfluidic device capable of such a test. Jim Heath makes parallel nanowire arrays, functionalized with a capture agent (Ab's or nucleic acids). Ligand binding changes capacitance, proportionally to concentration of ligand. Heath has shown dynamic range of 106, and successful detection in physiologic salt concentrations. Capture agents might be made using “click chemistry”, where good antibodies could not be generated.
The Four P's of Systems Medicine Predictive: The 2000-biomarker test, combined with the patient’s genome sequence, would provide early detection for most diseases, or an assurance of health. Preventive: In addition to therapeutic drugs, we will have preventive drugs for diseases you don't have yet. Drugs may be prescribed not by diseases, but by protein target, including a personal assessment of off-target hits (side effects). Personalized: Only 6 million nucleotides are different between individuals, easily catalogued in individual’s medical genome record. Treatment will be individualized; and will focus more on maintaining wellness than on ameliorating disease as medicine advances. Participatory: Because more complete knowledge provides clearer diagnoses, and outcomes are more well-understood, the patient can understand and make medical choices that now require experts. Predictions of the Future Looking at a roadmap of the steps necessary to realize this vision, it is clear that it cannot be done by RO1 science alone, but will require strategic partnerships between academic, government, and commercial efforts.
P4 medicine will be cheap, and available to the
entire world. |
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