The route of science: Labyrinths and algorithms - Inspirations by human papillomavirus testing and cervical cancer

Popper's landmark work, Logik der Forschung (The Logic of Scientific Discovery) (1959), starts with the lines: “Without a doubt, the collective scientific knowledge of mankind is the greatest miracle of the world.”[1] According to Popper, a theory should not only be “verified” but should also be “tested” and even “objectified” for it to be considered as scientific. He argues that pursuit of knowledge is only possible because of the objections to and versatility of said knowledge. Popper remarks that “when referring to human knowledge, he will usually have this objective sense of the word ‘knowledge’ in mind.”[2] These concepts are clarified in the following lines:

The falsification of the prediction shows the explanation is false, yet the reverse of this does not hold. It is incorrect and grossly misleading to think that we can interpret the “verification” of the prediction as “verifying” the explanation or even a part of it, for a true prediction may easily have been validly deduced from an explanation that is false. It is even quite misleading to regard every “verification” of a prediction as something like a practical corroboration of the explanation. It would be more correct to say that only such “verifications” of predictions which are “unexpected” (without the theory under examination) may be regarded as corroborations of the explanation, and so of the theory…[2]

Popper states that researchers are often too blinded by facts to deliberate on the meaning of these facts. He contends that seemingly useless bits of uncovered information can, in the long-term, with the help of additional innovative information, help in solving puzzles or creating mosaics to discover the complete meaning. Popper's view was further developed by Kuhn, Feyerabend, and Lakatos. On the other hand, according to Maxwell,[3] who opposed this view, “…Science dissociated from the pursuit of wisdom, (is) the result of our failure to put right the structural defects in academic inquiry, inherited from the blunders of the enlightenment.”

Humanity's advancement in the field of science throughout the course of history can be likened to infant taking steps in a huge Labyrinth [Figure 1]. Getting closer to one's destination in a Labyrinth does not necessarily mean that the correct path is being followed. The progress of human knowledge is a result of the tireless wanderings of scientists through the Labyrinths of truth. For thousands of years, humanity has been mapping new frontiers, discovering new Labyrinths, and finding new avenues of the doubt. Thanks to this unending march, we are able to devise new explanations and algorithms to guide our way.

The concept of the Labyrinth is deeply etched in mythology reflecting humanity's shared consciousness in seeking to find ways out of seemingly impossible situations and to reach a goal or truth through the innovation and perseverance. The Minoan culture of Crete was associated wıth the double-headed axe or Labrys and of course it was there that the classical Labyrinth was built for King Minos at Knossos to house the fearful beast called the Minotaur. The Athenian hero Theseus was able to find his way to the center, slay the monster, and find his way out again by retracing his steps with the help of a ball of string. In Greek mythology; the double-headed axe, Labrys was wielded by Zeus. One side pierced through the darkness while the other side was used to split the head of the creator god Zeus himself, scattering the light trapped inside him, and giving birth to Athena, the goddess of wisdom. In modern usage, a Labyrinth is an intricate combination of paths or passages in which it is difficult to find one's way or to reach the exit.

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Figure 1

The Labyrinth

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Scientists were the first to discover the Labyrinths that we call paradigms and introduce them to the light of day. Pioneers take the most difficult paths in the darkness of uncharted territory before others have the courage to do so. Those following in their wake can thus find the way and draw up the maps. Once the enlightenment at the end of the Labyrinth has been reached; graphs, flowcharts, and algorithms must be created in order to enable others to use this knowledge without losing their way.

Therefore, a scientist focuses on where a particular piece of knowledge fits into the grand puzzle, but he must not be in a rush to view the grand picture. On the other hand, as science is inevitably involved with industrial and commercial interactions; skepticism may be seen as a waste of time by those who are pressing for urgent application of this knowledge. The path leading to the greater good may be seen as a diversion by those with the profit idea in mind. For them, turning knowledge into a product without delay may be perceived as the priority. An example of the latter can be seen in the case of new drugs that hit the market with much ado, but are later forcibly recalled after the revelation that they had not been properly tested.[45] These labyrinthine roads which lead to blind alleys are being increasingly publicized. This situation can result in public disappointment and, unfortunately, in a distrust of science and scientists.

In recent years, medical science has witnessed an explosive growth in the recognition and understanding of the molecular genetic abnormalities that drive the development and progression of various cancers. Furthermore, the therapeutic relevance of these abnormalities mandates that molecular testing be performed in order to facilitate management decisions. Therefore, to ensure timely and appropriate patient management, the judicious and effective integration of molecular ancillary testing with cytopathology specimens is called for Human papillomavirus (HPV) testing on cervical cytology specimens is one of the salient examples illustrating the intimate interface between cytopathology and molecular diagnostics.[6]

The molecular biology of the papilloma virus family is a rapidly developing field. Since the 1970s, special attention has been given to their interactions, which lead to benign or malignant proliferations, with emphasis on human cancer.[7] The HPV relationship with cervical cancer has provided significant hope for a breakthrough in the struggle against cancer in the last decade.[8] Moreover, with the expectation of preventing cervical cancer, the proliferation of HPV tests and vaccines on the market has accelerated, despite the fact that it is too early to evaluate the outcome in terms of cervical cancer incidence and mortality rates. As a “reflex test” in the triage of low-grade epithelial abnormalities, high-risk HPV (hrHPV) testing has improved the patient pathway by reducing unnecessary referrals and returning women to normal recall much earlier. Similarly, as the “test of cure” in high-grade cervical intraepithelial neoplasia, hrHPV testing has greatly improved patient management and has been highly cost efficient.[9] However, in spite of a considerable amount of hope and anticipation, the results of the first trials have not been quite what was expected in terms of the acceptable specificity of hrHPV testing for intraepithelial lesions[1011] or even for invasive cancers.[1213] This may possibly be due to several parameters such as the episodic nature of HPV infections, L1 deletions, molecular biology of early invasive lesions, or the variety of sampling methods.

In addition, unnecessary surgical interventions may have increased because scientists have been trying to make advanced analyses to determine the viral agent, which is highly capable of presenting temporary and mostly reversible appearances. With time, concentrating on hrHPV testing as co-testing or HPV-only primary screening modality; instead of the time-honored algorithms based on Papanicolaoutest may demonstrate an effect on the treatment of cervical cancer. For the time being; the best hrHPV test, the most appropriate cut-off value, testing algorithms and the right collection media needs to be determined through scientific falsifiability and its requirements of being tested, verified, and objectified.

In the context of the “architecture of knowledge” objectified knowledge is explicit, codifiable, transmittable without bias, through the language, and generic. It refers to knowledge that serves as a platform to investigate new empirical phenomena. Blackler refers to this category of knowledge as “encoded” knowledge. As it is indicated by Amin, objectified knowledge corresponds essentially to the “know-why” in Lundvall and Johnson's typology (referring to the scientific knowledge of principles in the human mind and in society).[14] As Popper pointed out, in order to remain within the bounds of scientific and critical thinking required by falsifiability; the criteria of testability, verifiability, and objective evaluation must be met. The most striking example of the application of these criteria in the last century can be seen in the discovery of the Higgs field and Higgs boson. Peter Higgs put forward the beginnings of a scientific theory in 1960s in which he proposed energy conversion material particles. The particle theory of transformation which allows for the energy of the material particles to be produced independently from one another was investigated by repeated experiments with two different teams. These experiments (ATLAS - A Toroidal, LHC Apparatus, and CMS experiments) along with the theory exhibited the capability of being tested were open to transparent evaluation of the data obtained and were bound by objective evaluation criteria. Furthermore, attempts were made at falsification. However, ultimately, the key agent particle in energy conversion (the God particle) was discovered.[1516] The existence of the Higgs boson has been nearly universally acknowledged and as a mere observer of the process, Peter Higgs received the 2013 Nobel Prize in Physics for his theory.[17]

The current era of personalized “precision medicine” continues to evolve at an accelerated pace. Thus, effective multidisciplinary collaboration and coordination amongst cytopathologists, surgical pathologists, molecular pathologists, and clinicians becomes even more essential. The ultimate goal of these multidisciplinary efforts is to devise “best practice” approaches, with the selection of appropriate molecular tests while avoiding inappropriate and unnecessary testing. Within the setting of escalating health care costs associated with laboratory testing as well as with targeted therapy, the judicious and effective use of molecular tests is paramount.[6]

Scientists must continue their unrestricted and also skeptical research to find the truthfulness of the new route in the “Labyrinth.” Some may see this scientific skepticism concerning research as an unnecessary indulgence. However, “skepticism” has been the traditional way in which humanity has developed scientific knowledge throughout the centuries.

Skepticism is not a position, but the process of applying reason and critical thinking to determine validity. The scientific method requires evidence, preferably based upon validated testing. In the case of “HPV and cervical cancer,” skepticism is a meaningful component also in clarification of the “correlation proving causation,”[18] since the testing of which is not yet accepted as being “state-of-the-art” or the “best practice,” as a primary screening model.

The desire of a scientist is to continue uncovering Labyrinths, to find the correct routes using algorithms and to continue living by the principles of scientific thinking, with the goal to serve mankind in the light of wisdom, hopefully without time constraints or industrial pressures.

COMPETING INTERESTS STATEMENT BY ALL AUTHORS

Both authors declare no competing interests.

AUTHORSHIP STATEMENT BY ALL AUTHORS

Both authors of this article declare that they qualify for authorship as defined by the ICMJE. Both authors are responsible for the conception of this study, have participated in its design and coordination, and helped to draft the manuscript. Both authors have read and approved the final manuscript.

ETHICS STATEMENT BY ALL AUTHORS

This manuscript is in form of a letter. Therefore, institutional ethical approval is not mandatory. The caricature is original, prepared for this manuscript.

LIST OF ABBREVIATIONS (In alphabetic order)

HPV - Human papillomavirus

hrHPV - high-risk Human papillomavirus

EDITORIAL/PEER-REVIEW STATEMENT

To ensure the integrity and the highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through automatic online system.