What is precision treatment and how did it change? Treatment
follows an evolutionary course.
Syphilis was treated by mercury, then Salvarsan then Penicillin G.
Dropsy by leeches, then Digitalis, now treatment is aimed at underlying
causes: IHD, Valvular disease, cardiomyopathy, hypertension, diabetes
mellitus.
Diabetes mellitus by a low-starch diet and vigorous exercise, or an
herbaceous blend of lupine (a legume with edible peas and gaudy flower
spikes), fenugreek (a small herb with pungent yellow seeds) and zedoaria
(a wetland crop whose roots taste like ginger with a bitter aftertaste,
then insulin. Progress to GLP-1 for type 2 diabetes
All these are increases in diagnosis and treatment: This is precision
medicine during the last 2.5 millennia. Thus the approach is same wine,
new bottle.
Today the leading contenders for inclusion in precision medicine are
suggested by biogenetics, microbiomics, epitope alterations, lifestyle,
co-existing disease, ethnicity, sex, age, the factors that most
physicians practicing medicine would consider in order to diagnose and
treat disease. It is a holoscopic rather than meroscopic approach, as in
precision medicine the use of artificial intelligence, relying on AI and
a mechanistic appropriation of data points. But diseases evolve so
population-based data require real-time processing as evolutionary
changes occur.
Is precision medicine’s mechanistic approach sufficiently different to
change medicine ? Has not the increase of specific treatment always been
the aim? Is this not historically the case?
Consider complex systems; ‘the butterfly effect’ Would the microbiome or
the co-existence of depression, hypertension or diabetes influence this
complex system? Would precision medicine make the categories more
precise in e.g. DSM-5? ICD-10? Perhaps, and that is welcome as
specificity has always been the aim. But AI and machine learning must
account for evolutionary changes in disease. The data base would need
continuous updating.
Precision medicine promises to establish more precise classifications
for diseases, especially, recently, for malignant tumors, by applying
more specific data derived from biogenetics. For example in a recent
partnership between a pharmaceutical company and a cancer center, 10,000
cancer patients’ tumors were further analyzed for actionable mutations
that would suggest further clinical trials to identify treatment
options. When subtypes of tumors were further classified there were too
few identified similar tumor subtypes to proceed to a trial. Precision,
perhaps? But too many classes. It might be possible for a cooperative
study and new classification if recruitment of sufficient number of
patients with a sub-subtype were to be identified nationwide or
worldwide. Genetic tumor markers, permutations, identify classes of
tumors that are not usually recognized in the ICD-10 classification and
this may be the role of precision medicine? This in order to treat
non-responders (the participants whose tumor markers (are different from
the majority) in Phase III clinical trials.
On the contrary medicine promulgates that we ought to treat theperson with the disease and not the data points of a disease, not
a mechanical application of data. Observations confined to
data-point-generated concepts are blind. There is no disease without a
concept, in spite of an array of data-points. Personalized medicine
relies on a conceptual model of disease based on physical examination,
pathophysiology, imaging, laboratory tests experience, and large
clinical trials or meta-analyses of trials.
Without the conventional classification of diseases, e.g. ICD-10,
precision medicine would entail innumerable classes of diseases. There
would not be a class that contains 1.infectious 2.parasitic,
3.malignant, or 4.degenerative diseases. Each disease subtype would be
in a separate class. There might be no class that contains all malignant
lymphoma subtypes. Lymphoma now lists more than 60 subclasses.
Precision medicine would consider each patient’s measurements to exhibit
a separate distinct disease, a class made up of one
patient by collecting innumerable distinctive data points of its own
without overlap: no projectability from one disease to a similar
disease, nor from one individual to another. This would allow treatment
unique to that person’s disease who does not share a class with other
patients. But artificial intelligence and machine learning depend upon
large data sets, upon population-level data.
Precision medicine treatment is not feasible because medical evidence is
based on general tenets, induction, derived from current diagnostic
criteria (perpetually undergoing refinements, clinical trials and
epidemiology applicable to all or most patients within the disease
class.)
Diseases are not stable entities but evolve during treatment to resist
treatments, the modal nature is altered by treatment e.g. MRSA,
influenza, cancers. the origin of tuberculosis in the middle East is at
least 9000 years old1113 Hershkovitz, Israel; Donoghue,
Helen D.; Minnikin, David E.; Besra, Gurdyal S.; Lee, Oona Y-C.;
Gernaey, Angela M.; Galili, Ehud; Eshed, Vered; Greenblatt, Charles L.
(15 October 2008).”Detection
and Molecular Characterization of 9000-Year-Old Mycobacterium
tuberculosis from a Neolithic Settlement in the Eastern
Mediterranean”. PLoS ONE. 3 (10): e3426. and common
resistant mutations are numerous, Thr(ACA), Asn(AAC), Ile(ATC),
Thr(ACT), Gly(GGC) inhA promoter -15T and evade drug therapy.
Just as coronaviruses have become the current entity to manifest
evolution and transmission across species.
Malaria has defied cure based on the point mutations and gene
amplifications e.g.crt, dhps, dhfr, mdr1, and even artemisinin resistant
malaria mediated by point mutations attributable to Kelch13.2214Menard D, Fidock DA. Accelerated evolution and spread of multi-drug
resistant Plasmodium falciparum takes down the latest first-line
antimalarial drugs in southeast Asia. The Lancet, Vol.19, issue 9, p
916-17, 2019
15Zhao Y,Liu Z, Soe MT. et al Genetic variation associated with drug
resistance markers in asymptomatic Plasmodium falciparum infection in
Myanmar.Genes,Vol.10 Issue 9, p 692, 2019
16 Darwin C. The origin of Species. (Variorum text) Chap 14. P 760.
EBV sequesters in B cells and silently reproduces only to remain viable.
Herpes hides in neural ganglia for many years until opportunity arises.
Our taxonomy of disease is based on observations that, given signs and
symptoms, diseases reflect the relationship between the disease, its
cause and resistance to interventions, natural and therapeutic, and the
patient’s pathophysiology; each patient manifests symptoms and signs
that mimic, but do not match exactly those in others with the same
disease.
Disease classification is a homeostatic cluster of features that
distinguish it from related diseases. “We carve nature at its joints.”
accordingly.
Leukemia requires a predicate, a sortal predicate if you will, thus ALL,
AML, CLL, B-cell lymphomas are categories of the disease, yet antigenic
markers distinguish among these diseases to allow targeted therapy, e.g.
based on cytogenetics and therapeutically on molecular markers KIT,
FLT3-ITD, NPM1, CEBPA, PD-L-1, CD-19 perhaps CD30.
As our nominative classification of these diseases is based on testing
for the antigen expressions, and as therapy induces changes in the
cellular expressions, so tumor cells become resistant to further
elimination by transmutations to acquire resistance; surviving clones in
minimal residual disease (MRD.) Discrete classes, carved at their
joints, provide more specific treatments. Or so it is hoped. The
mechanistic approach of precision medicine is here applicable. But the
measurements required to perform to characterize a condition are on a
asymptotic curve.
Evolutionary changes in the body, dependent on both external and
internal environments, allow diseases to escape the immune system as
illustrated above. Tumor cells evolve to become refractory to
chemotherapy. Loss of responsiveness to treatment with monoclonal
antibodies (mAbs) such as
rituximab is a serious complication during therapy of B-cell
malignancies but the mechanisms responsible for it are not well
understood. Even CAR-T therapy directed against CD-19 has not shown
success in all cases of leukemia and lymphoma; CD30 is a promising
alternative antigen target. BTK inhibitors such as ibrutinid may play a
similar role in some
non-Hodgkin’s lymphomas.
Clones of tumor stem cells evolve to resist intervention.33
Molecular evolution, even in laboratory-controlled constant supporting
conditions are determined by stochastic processes. Escherichia coli
mutation and was measured over 60,000 generations showing only a slight
decline in fitness; and these changes were balanced against multiple
beneficial variants.4417.Good B.H., MaDonadl M.J. et al. The
dynamics of molecular evolution over 60,000 generations. Nature 551, 2
November 2017,;4550
Thus, generalizability (induction) is forfeited to particularity,
sensitivity to specificity, and randomized controlled trials would
suffer from lack of participation since each disease would be treated
somewhat differently, depending on the definition based on the character
of the disease, genetics, as well as on the sufferer. Thus, precision
medicine would usurp the medical treatment available based on randomized
controlled trials and would evolve into ‘customized’ treatment.
Treatment protocols would be suited to the genomic markers of the
disease and these degrees of difference might require different
therapies. This would eventually and controversially obviate the need
for randomized trials
Research options :
In place of RCTs precision clinical trials might include n of 1, or even
master protocols such as umbrella and basket trials. One SNP does not
make an entirely new disease. That is the foundation of umbrella
protocols, Tumor cells regulate antigenic self-expression in order to
survive the treatment by protocol drugs, and they usually succeed. Even
ALL is not vanquished, thus CAR-T Therapy. Yet which tumor cells to
search? which fluid biopsies of CTCs or ct-DNA to sort and harvest and
insert a chimeric antigen?