Ribonoscopy and “Theragnostics” - Molecular Theory of the Living Cell - page 602

(Please note that the number of RNA molecules being analyzed is thought not to
affect the conclusions to be drawn as long as they are greater than about a dozen.)
Panel b is a simulated ribonic spectrum of the same set of RNA molecules as Panel a
but of the cells in a diseased state measured with the same microarray used in
measuring the ribonic spectrum of the normal cell type. When the ribonic spectrum
of the normal cell is subtracted from the ribonic spectrum of the diseased cell, a
difference ribonic spectrum (DRS) is obtained as shown in Panel c. It is predicted
that different diseases will exhibit different difference ribonic spectra . If proven
correct, DRS can be employed as “disease-related biomarkers.” The DRS can also
be employed to characterize the disease-related cell states. Any drug candidate
(pure or composition unknown) that has the ability to “flatten” or “abolish” the
difference spectrum (see Panel d) can be selected as the drug candidate for the
disease under investigation.
It is important to keep in mind the following features of the ViDaExpert
program:
The ribonic space on which the ViDaExpert program acts must contain the
microarray data (i.e., ribons in Table 18.1 ) measured from all three samples , that
is, the normal , and the diseased before and after drug therapy , since the topology
and hence the node number assigned to each ribon in a ribonic spectrum is the
function of the number of ribons in the ribonic space. In other words, it is not
allowed to apply the ViDaExpert program to the three samples mentioned above
individually and then try to obtain the difference ribonic spectrum by subtracting
the normal ribonic spectrum from the diseased ribonic spectrum.
Since the frequency distribution of ribons over node numbers sensitively
depends on the number of the points (or ribons) in the ribonic space, the stretching
coefficient and bending coefficient (Eq. 12.20 ), at least a part of the “flattening
effect” of drug on the difference spectra (i.e., the transition from Panel c to Panel d)
can be accidental. Such accidental or random effects can be detected and removed
by running the ViDaExpert program on the ribonic space of three samples as many
times as is needed to correct for random changes.
The difference spectrum, Panel c, can be used as a companion diagnostic tool to
identify the patient who can benefit from a drug and who cannot by observing
whether the drug “flattens” a patient's difference spectrum. Those patients whose
difference ribonic spectra are not flattened by the drug under investigation can be
excluded from clinical trials, which will decrease N in the equation shown in
Fig. 19.1 , thereby increasing the success rate of a drug for FDA approval.
The drugs discovered by the ribonoscopic method described here can be named
as “dissipative structure-targeting drugs (DSTDs)” or “dissipaton-targeting drugs
(DTDs),” since they are identified through their effects on either ribons (Figs. 19.1 ,
19.2 , 19.3 ) or difference ribonic spectra (Fig. 19.4 ) which are all examples of
Prigogine's dissipative structures or dissipatons (i.e., no ribonic difference spectra
can be obtained when the cell system involved dissipates no free energy).
Although it is generally accepted that microarrays, as commonly used, measure
RNA levels in cells indirectly by measuring the cDNA synthesized from the RNAs
isolated from cells (see Fig. 12.5 ), there are important differences between the