First Draft 16/02/06 Text: 31,789 words; References: 3,169 words; Total: 34,958 words
“Reflections on the Scientific Method in Medicine”
R.J. Stusser
Former Consultant Researcher and Professor of National Research Centers of Havana University, Ministry of Public Health, and West Havana Scientific Productive Pole, Havana, Cuba.
Keywords: science, medicine, scientific method, scientific research, clinical medicine, clinical judgment, biomedicine, public health, humanities, scientific policy, scientific paradigms, research program, mathematics, technology
Content
Summary
1. Introduction
1.1. Needed Historical Frame
1.2. Reflections Presentation
1.3. Five Principal Hypothesis
1.4. Objectives and Methods
2. Beginnings of the Scientific Method in Medicine
2.1. Methodological Basis of Pre-Scientific Medicine
2.2. Methodological Launching of Scientific Medicine
2.2.1. Technological and Scientific Revolutions
2.2.2. Scientific, Logical, and Philosophical Bases
2.3. From Reason and Dogma to Probability of Facts
3. Advancement of the Scientific Method in Medicine
3.1. Inharmonious and Disproportionate Progress of Medical Sciences
3.2. Logical and Methodological Problems of Clinical Medicine Sciences
3.3. Restoration of the Old Natural and Traditional Clinical Medicine
4. Methodological Complexities: Some Controversial Case Studies
4.1. Oxygen as a Cause of Blindness in Premature Infants.
4.2. The Chemical Bases of the various AIDS Epidemics.
4.3. Rethinking Clinical Proteomics after Setback.
5. Suggestions to Improve Medical Scientific Methodology
5.1. Creation of an Integrative Methodological Research Strategy
5.2. Use of a Recombinant Hypothesis Discovery Support System
5.3. Use of a Modeling and Simulation Research Design Optimizer
5.4. Enhancement of the Clinical Scientific Hypothesis Creativity
5.5. Underlying Theoretical and Philosophical Problems of Medical Science
6. Isolated Medicine Scientific Research Methods and Strategies
6.1. Clinical Ortho-Investigation Crisis before Meta-Investigation
6.2. Clinical Science Methodological and Philosophical Hurdles
7. Unified Methodological System for Investigation in Medicine
7.1. A Trans-Methodological Model of Clinical, Basic and Health Sciences
7.2. Re-Unification of Clinical Scientific Method for Practice and Research
8. Conclusions and Recommendations
Bibliography
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Summary
The aim of this essay is to meditate on the concept of a comprehensive scientific method to care the individual patient, teach medicine, and make scientific clinical research more creative and fruitful, strengthening its internal logic of progress. In the last 60 years, medical research has suffered a crisis of efficiency in its effort to achieve the humane goals of medicine. This research has faced the multiplication of its costs, apart of the costs of a more technological medical care, disfavoring the clinical ortho-investigation of high quality induced from inside the clinics, originated-in-the-patient, and investigator-driven. Clinical progress is being practically achieved through clinical meta-investigation, mostly induced from outside the clinics by the technological sophistication process, by the risk factors, disease, and death indexes decline and less by the health favoring factors, healthy lifestyles, and total and healthy life expectancy indexes increase. The essay is directed to motivate much more for scientific research the new generations of students of medicine and science, clinical and family physicians, surgeons, psychiatrists, dentists, professors and investigators, as well as other scientists, mathematicians and philosophers. It begins with a brief historical framework with a broad approach that may give the first impression that is going out of the matter. The paper goes on meditating through several issues, exemplars, insights, hurdles and challenges of the application and adjustment of the scientific method hypothesis-driven (previously developed in the physics) in clinical medicine. This is conceptualized as a special science of particularities and generalities too, now a huge empirical research domain but a still too little theoretical research realm yet, in intimate relation with the pre-clinical and post-clinical dominions of medicine. It specially examines the complementarity of an integrative inductive-deductive theoretical research strategy for discovery of new medical hypotheses, and of two computerized knowledge- and data-driven systems: one, for discovery of recombinant hypotheses from knowledge databases, and other, for optimization of research design through human modeling, simulation, and prediction. Using scientific intuition and system analysis it gives some suggestions of answers to delicate, difficult and critical questions in the application of the scientific reasoning and method in clinical medicine, for the strengthening and completion of its scientific foundation, the weakening of the irrational anti-science movement against it, and the benefit of the clinical care of the individual patient. Some enlightening insights on medical probabilistic and determinist systems, as well as in the medical body-mind problem, received special attention too, both in relation with the systems of physics. It lets the verification of the few suggestions of answers given and the rest of the numerous unanswered questions stated, for the next generations of physicians, scientists, mathematicians and philosophers that will multiplied exponentially the progress of scientific medicine in the current century. It concludes that a unified scientific methodology with a solid foundation could be created for the clinical medicine, to promote more in depth scientific research, discoveries, invention, and innovations for the patient's good.
1. Introduction
1.1. Necessary Historical Frame
To be able to understand well with a realist view the beginnings, advances, trends, limitations, and challenges of the scientific method in medicine in the 21st century, it is indispensable to state exactly the human development historical context of the practice of medicine, of science in general, and of the particular science of medicine with its three branches of medical sciences, of their allied sciences, and of the scientific attitude, thought, objective and method.
Human ignorance, worst health, and nasty, brutish and short life has changed dramatically with economic development from the prehistory to ten millennia ago, when it arose the agriculture and practically all people had to survive unending epidemics, famines, miseries, local wars and political despotism with very primitive knowledge, technologies, sanitation, and natural and traditional medicines that did not help. From those times to around the mid-1700s, there was a very slow change for the better but most people still lived with ignorance, ill health and ill life advancing from extreme through moderate to mild poverty. Then, the differences between the living standards of Europe, America, Australia, New Zealand and Japan were from 2-1.5 to (:) 1 with South and East Asia (India and China), to 4-3 to (:) 1 with still primitive regions of Africa, Asia-Oceania, and Latin America. Rulers, large landowners, and traders began to live better in affluence due to better knowledge, technologies, sanitation, and medicine, but not based on enough scientific evidences yet. The differences between rich and poor was in general from 5 to (:) 1 [1-5,0].
However, from the world’s 900 million people in 1750 to the 2000s, merely 250 years, an extraordinary and almost global market-based international economy and social self-sustainable development have spread industrialization, wealth, democracy, technological-scientific progress, international trade and foreign investment, and an increasing medium class coming from the falling poor class. In the 20th century, the Great Britain and about 20 capitalist nations —most of them former colonies of empires— experienced a quick development, but most of the countries was left behind due to diverse geographic, cultural, historic difficulties, colonial exploitation, and autarchic policies behind ineffective trade barriers, still in study. These industrial modernization was very hard and difficult, and however, have also brought about an almost globalization of environmental degradation, wars, ideological subversion, and terrorism [1,2]. Already in the 20th century, Russia, after being developed was self-retarded and re-impoverished again, and actively retarded the globalization of the economic growth and self-sustainable social development and re-impoverished the world, advocating in the developed and developing countries for the alternative theory of socialist development. This development model apparently more social and fair, it was only in theory more human and efficient, because in the practice, it resulted unsustainable and it self-extinguished in 1991, due to its elimination of the individual and market economy liberties.
It has been estimated that if Africa would have followed the free-market policies of the East Asia governments (Hong Kong, Singapore, South Korea, Taiwan, Thailand, Malaysia and Indonesia), its annual average rate of growth per head between 1965 and 1990 would have reached 4.3 %, trebling the incomes. The actual rate was a mere 0.8 %. Today the difference of living standards between North America and Africa is around 20:1, because the first maintained a sustained growth rate of 1.7% for more than 200 years [11].
Mainly in the 20th and beginnings of the 21st century ignorance, ill health, hunger and poverty have been more than halved, life span and living standards have been more than doubled, and the difference between rich and poor was reduced, although still continues the need for more social justice and the attention to what people feel.
Nevertheless, these advances have come accompanied with global confusion bringing setbacks in economic and social matters as well as in science and medicine. In the scientific clinical medicine systems in the 20th and 21st centuries, it was restored in the most developed countries the whole spectrum of the pre-scientific medicine remedies and techniques, even since the prehistory to the 19th century once again. Only in USA in the 1990s, the estimated number of visits to these unconventional medical providers was 425 million/annum with a cost out of pocket of $10.3 billion/annum, exceeding the 388 million visits to US primary care physicians, being the cost of all US hospitalization of $12.8 billion [6].
In 2005 of the world’s 6.3 billion people still live one half in closed overbearing systems and 40% in poverty --including one billion in extreme poverty (daily incomes < U$S 2,00) and 1.52 billion in moderate poverty (daily incomes < U$S 2,00). Like their ancestors in the 1750’s, they still suffer the ignorance, ill health, ill quality of life, and lack needed education and health care, in spite of the existence of oceans of wide and deep knowledge, highest-technologies, advanced sanitation, and total or partial effective scientific medicine for most illnesses known [1].
The persistent fossil infectious epidemics in the poor countries together with the latest emergent ones, are conspiring at the global level not only against the health of the world poor population, but also against the best health of the wealthy and medium classes in developing and transitional countries, and even of the most developed countries (without extreme poverty), in total around 2.78 y one billions people, respectively, besides their own specific burden of chronic non transmissible illnesses of the affluence.
The clever option is not to go back to a previous socio-economic and techno-scientific period again. It is not to recede in health care to all the primitive and pre-scientific medicine remedies and techniques again. Instead to retreat, the developed and developing countries with the guide and help of the most wealthy and advanced countries should find the way to adjust a autosustainable economic and health care growth and development, with the less suffering of the whole population and environment, using the vast possibilities of the modern economic and medical systems and of the material-energy and information-communication technologies.
1.2. Reflections Presentation
Usually in most world universities when the medical school undergraduate students and residents learn the scientific method to know how they can research in medicine, most of all they receive from their faculties a short introduction to a universal abstract scientific method with schemes of how to make and write a research design, report, presentation, and article of empirical results. This is followed by a long, abstract, and detailed exam of mathematical statistics estimation and hypothesis tests of proportions, means, standard deviations, correlation and regression coefficients; non parametric statistics, tables, graphics, statistical software; some times even Gaussian and Bayesian probability theories, besides analysis of variance, multivariate analysis, and so forth; to quest for medical certainty, in the results of medical surveys and trials, and without a medical science and research specific orientation.
It is given the scientific method in a finished form that it seems that has ever existed very strong in one piece, along with the statistical techniques, as the (only) technology of the scientific method in medicine they need to investigate. However, the origins, application and development of the scientific method in medicine and medicine scientific foundation are much more serious and not exempt of methodological particular and singular complexities and flaws incompletely understood yet. Scientific research in medicine is much more than the simple use of a universal and abstract scientific method assisted by statistical procedures and software, as for example in agronomy and veterinary, because it involves the human being.
This abstract statistical inference trend began in the late 18th century when in medicine most physicians did not like the intrusion of mathematics, but also due to medicine complexity and immaturity, they could not put clear their scientific algorithmic and heuristic methods in the take off. In 1946 after debates for a century, was first accepted medical statistics when the British physician-statistician Austin Bradford Hill made the first randomized controlled clinical trial of streptomycin in tuberculosis, beginning to move the pendulous to the other extreme for the last 60 years. Since then, the scientific credentials given by experimental physiology and bacteriology laboratory techniques to medical research from the 1840s to the 1940s, were given by nearly experimental statistical techniques to clinical and epidemiological research [7], being considered clinical art and technology all the rest. The medium just in clinical research it seems that will be achieved when the pursuit of clinical relevant results by a clinical, surgical or psychiatric investigator with a more explicit creative and powerful method retake again the scientific leadership in clinical research, assisted in the statistical measuring and confidence issues by a statistician who understands clinics. This will be possible when in the new generations of physicians also arise full time theoretical clinical investigators to work besides the clinical investigators who work only with the logic of facts since two centuries ago.
The scientific method in medicine must be studied more dynamically in conjunction with the great spectrum of medical empirical research methods, which use the supplementary statistical techniques to handle the data of scientific facts, with the no less important and even so or more creative medical rational research methods of the scientific medical hypothesis, theory, and law too [8,9]. The latter have been very little handled by most medical researchers, with the exception of the French physician-physiologist Claude Bernard. The conceptual and operational framework needed to be able to use the whole scientific method power in clinical medicine for practice and/or research objectives, presupposes the existence of a minimal scientific very critical and creative scientific attitude, thought, reasoning, goal, strategy, and program expressed in the universal scientific literature and experience. The first step of examination of the guiding research problem and hypothesis should be the study and design of a complex matrix of facts and ideas, in such framework, without excluding neither empirical nor rational elements [10]. Afterwards, there will be enough time for the guided selection and design of the auxiliary statistical matrix with the sets of variables and group(s) of patients. This design must be made as well as the conduction and analysis of the scientific results of the survey or trial, by the clinical investigators aided by the clinical statistician.
The 21st century high level scientific medicine that we know today is the global outcome of a long historical and logical progress in the axiological and ethical pursuit of the scientific truth and objectivity of the scientific knowledge and technological safety, efficacy and efficiency in the health care process. This trust in science has been achieved applying, adjusting, and developing a trustworthy method for the progress of the technological arsenal and scientific body of knowledge needed by the practice of medicine and scientific research in medicine. With this scientific method has been obtained the huge body of countless technological, empirical, and theoretical results most accurate to the real benefit of the individual patients, with an acceptable degree of medical certainty by the world medical scientific community.
Medicine has evolved from instinct and experience in prehistoric times to observation and reasoning in the Hippocratic Coan school period, to formulation of theoretical proto-scientific systems by --the Cnidian School--, Galen, --Avicenna, and John Brown--, and scientific experimentation in the 19th century. Philosophically in science and medicine, Aristotle and Rene Descartes’ rationalism were challenged by Francis Bacon’s empiricism [11], being both types of scientific methods reconciled by Isaac Newton and Emmanuel Kant, as was miscarried the embryo of Bernard’s determinism by the Pierre Laplace’s indeterminism.
Nevertheless, in spite of the great advances achieved through the progressive application of the scientific method and medical statistics in medicine, this is not free yet of great flaws, inconsistencies, and challenges, especially in the practice and research on clinical medicine, first and major branch that gives scientific foundation to the health care of the individual, family and community, with the most cognitive inter-level complexities of all known sciences.
That is why medical scientific research in the last 60 years continues being subjected to heated debates in the ethical, ontological, and epistemological fields throughout the world, trying to balance ambitious goals with limited means. The discussions take place among physicians, investigators, policy makers, industrial managers, philosophers, theologians, and sick and healthy persons, trying to decide mainly upon medicine logic of progress [12,13]. One main polemic is about which research is more human-oriented, if high-technology research to cure disease and delay death or low or non-technological research to care and palliate patients, promote healthy persons and prevent them from becoming sick and disable [14,15]. Another major controversy is about which is more effective on a medium and long-term for human beings, if conceptual, complex, and expensive research to explain disease mechanisms and cure a little, or more operating, simpler and cheaper research to improve individual’s lifestyles and increase the preservation of health, including grounded theory, research-action and participative approaches [16-19]. The status of things has arrived to the extreme that some retrograde forces have stated to stop making scientific research at all [6].
Still today the most chronic methodological discussions in medical research continue, about the measuring of the partial research facts of the patient and their certainty, on the one hand, and on the clinical understanding and judgment of the integral research of the patient as a whole on the other [6,7,18-22]. The general clinicians, surgeons, and psychiatrists, after the amazing advances in material-energy high-technologies, statistical software and computing systems, molecular biology, genomics and proteomics, information-communication high-technologies that have taken place in the last 60 years, have intensified those debates along with sanitary colleagues of sociological background [22-24]. Nevertheless, the growing fusion –and/or confusion-- of technology with science that has arisen [25], has originated the acceptance of the randomized controlled double-blind clinical trials of industrial bio-pharmaceuticals, bio-devices, procedures and equipment, and more recently of natural and traditional remedies and techniques, as the only true and objective clinical research. However independently of the still incomplete use of the very powerful hypothetical-deductive method, the debate has not transcended enough the factual methods yet, to include the theoretical methods too [26,27], diluting the attention from its internal logic of discovery progress.
1.3. Hypotheses
This essay has five main hypothetical methodological hypotheses or principles:
1) Some scientific general problems still require integral scientific solutions that go beyond the limits of the present set of medical sciences and the simple articulation of their growing knowledge [II,28]. They could be achieved doing also a broad integrative scientific research strategy, using an iterative axiomatic-like method, complementing the necessary, successful, but not sufficient reductionist research programs. Thus, unifying principles within a general body of theory of a unified medical science might be obtained, and original emergent hypotheses might be revealed from them, structuring and concluding them, along with the induction of accepted theories and facts, using the insuperable hypothetical-deductive method [25].
2) Concepts about medical research and intervention (R&I) as well as about medical research and development (R&D), on the person and family, medical model and technology, at the clinical office, ward, surgical room, home in the community, at the basic or industrial laboratory, health service and system, at a medical knowledgebase, database or at an internet virtual net-clinic or net-lab, are related fields and moments of a unique creative process to solve scientifically problems, which could integrate multilaterally their scientific methodologies to achieve more scientific efficiency than when they are used only separately.
3) There could be a rapprochement across those partial medical research methodologies and approaches, which could include the empirical and quantitative methods of research linked with the rational and qualitative ones. It also could include more data-driven discovery support systems of recombinant hypotheses, and human pre-physical experimentation and prediction by modeling and computer simulation, and new ways of scientific hypothesis’ formulation, law-like generalization, and theory formation that would make medical scientific research enterprise more integral, and would allow establishing some scientific general methodological principles of clinical medicine first and of whole medicine later or vice versa [25].
4) Tacit ontological and epistemological principles of medical science, could be stated explicitly into the conceptual framework composed by sub-disciplinary, inter-disciplinary and super-disciplinary paradigms governing today medical scientific research, and could be also taught to enhance the scientific critical and creative thought, aim, and method in the clinical medicine scientist. Learning concepts, hypotheses, laws, and theories, in the practical way, but with an abstract approach too, would help the practical and empirical clinical investigators to guide and enrich their own research, as well as to the more theoretical ones too.
5) The integration and strengthening of clinical medicine research's own internal logic of progress, besides its strong external one, mainly depends on the re-conceptualization, re-flourishing, and scientific re-empowerment of the clinical judgment scientific method in a more explicit algorithmic method for practice, and renewed creative and heuristic method for research again. This should provide quite a powerful tool to attract many more young students, generalists and specialist giving them a better training in clinical research methods to face and solve the greatest scientific challenges that still is facing clinical medicine science, in the dawn of the 21st century for the benefit of the individual patient and family.
1.4. Objectives and Methods
If a half century ago, the Argentinean physicist-mathematician Mario Bunge wrote a powerful book of about 1,000 pages to demonstrate that the scientific method (in physics), was much more than statistical methods [8], serve this modest work on the scientific method in medicine to give some of the hints to develop a more comprehensive medical scientific methodology.
This essay pursues two main objectives:
First, to introduce and discuss the dynamic of the scientific method in medicine history, meditating polemically its logical, philosophical and ethical foundations, its complex operation with examples, and its main current strengths and weaknesses and future challenges for the future medicine progress, without any interest in being exhaustive
Second, to suggest a coherent and comprehensive scientific methodology framework to re-conceive, educate, and make clinical medicine research more creative and fruitful for the sick patients and healthy individuals, lowering expenditures, and strengthening its internal logic of progress with integrative research strategies besides the successful reductionist ones
The main material and method of the essay is as follows:
There have been studied intuitively and analytically for about forty years the most important world literature and experience in scientific method and logic, mathematics and statistics, philosophy and ethics of science and of the medical physical, biological, economic and social sciences, in hundreds of articles in journals, monographs and encyclopedias. There have been also studied thousands of scientific abstracts and hundreds of journal articles and monographs of concrete original research results and reviews of them in western clinical, basic and health sciences (including eastern Europe), in paper, floppies, CDs, and in Internet, mainly of the post World War II last 60 years.
The main historical, logical, ontological, epistemological, and ethical challenges of the future scientific thought, reasoning, goal, method, program and other means of medical scientific research constituted the framework of the reflections. The meditations have been addressed to essential theoretical problems of medicine scientific method’s spectrum of problems, and the problems are focused from the broadest angle (3600), instead of the smaller angles of scope of the usual approaches to the empirical problems in each one of the medical sciences.
A trans-methodological model of research was applied throughout the ample scope of physical and virtual sites where medical research is being made today to enrich the creativity of its isolated methods in use, never to supplant any of them. This work is very far from undervaluing any of the current methods and ignoring the pluralistic and relativistic nature of scientific knowledge. It attempts to seek the shortening of the time required for the encounter of outcomes of different medical scientific methods (the opportune moment to gain the scientific advance [16]), thus accelerating medical scientific progress in the patient benefit.
2. Beginnings of the Scientific Method in Medicine
2.1. Methodological Basis of Pre-Scientific Medicine
The practice of medicine has reached its ninth millenniums on the ancient India and less time in China, Egypt, Iraq, Palestine, Israel, Mexico, and Peru, among many other antique civilizations, although it was a practice that really started in the prehistory much more before than science. Medicine, surgery, and dentistry began as handmade faith healing activities on the patient based on instinct and experience, when death and disease were considered supra-natural phenomena. Medicine was also an art or technique to cure illness, relief suffering, and give comfort, impregnated of primitive mythical-magic, religious, and philosophical beliefs. Since its beginnings, medicine became served by a developing proto-scientific method allowing the accumulation of empirical knowledge observing individual patients, things that affect them, with a primitive cause-effect reasoning, and improving the patients with sorceries, natural substances, plants, minor surgeries, transplants of skin, reduction of fractures, within other means, advancing by the method of assay and error [11,30-33].
In Greece (5th century BC), Hippocrates, father of the western medicine in the Coan School, after incorporated eastern medicine knowledge, created the medical profession, considering the disease a unique natural state that can have many manifestations. He created a rudimentary clinical judgment method, interrogating, inspecting, palpating, and directly auscultating, the integral patient at the bedside. As an artisan he wrote in clinical histories subjective and objective symptoms integrating them in syndromes arriving to primitive diagnosis, prognosis, and treatments. He wrote on medical science and research, and about a “theory of humors” –in which disease was caused by imbalance of the body blood, yellow bile, black bile, and phlegm. He also wrote about the “wrong life” as a cause of disease. His findings were written without theoretical considerations in the “Hippocratic Corpus”, first medical encyclopedia. He founded the phenomenological scientific method to medicine [11,30-33]. By the other hand, in a more scholar way, the Cnidian school constructed abstract pictures classifying different diseases from the analysis of numerous cases, setting from theoretical hypothesis and deductions, dietetic and therapeutic principles, which were used to impose to the patients, disconnected of the clinical observation and experience [30,32].
Within the called western “Hellenistic scientific revolution”, Aristotle, father of biology, was a primitive empiricist, influencing medicine scientifically with his comparative anatomy and embryology, although afterwards his theories of teleology and rationalism became a medical dogma. The proto-medicine was divided in three big branches: 1. clinical medicine, surgery --and dentistry--, 2. epidemiology and hygiene, and 3. anatomy, physiology, embryology –also part of the proto-biology--, and pharmacology basic proto-sciences, beginning the relations with the exact sciences. One of his main works was the “Organon”. The Aristotelian causes of disease and health were of four kinds: material, efficient, formal, and final. Afterwards, Archimedes laid the foundations of mechanics, made the first scientific physical experiments, and unified physics with mathematics. Galen studied and wrote extensively adding something new to each medical branch. Described anatomy based upon pigs and monkeys, made the first physiological experiments, and formulated a complete proto-scientific system of medicine supplementing his findings by speculation. Galen wrote “The Art of Prescribing” [11,30-33].
For the next fourteen centuries of decadence and disregard of the Greek science, there were proportionately less contributions to medical science, because the scientific method based on empirical observations become undermined by philosophical dogmas and speculations. This situation began to change when the Arabs translated the scientific advances of Greece, India, Persia, and China, integrating them and developing theirs, and carrying them to Spain. The eleven hundred-year-old Qarawiyyin University of Fez, Morocco, is the oldest university in the world that is still functioning. Averroes and Maimonedes made many contributions, and Avicenna synthesized in “The Canon of Medicine” a proto-scientific system of medicine for medical practice. In this canon the physical and psychological factors, drugs and diet were combined. Medicine considered the human body as to the means by which it was cured when it was driven away from health. He said, “In medicine we ought to know the (Aristotelian) causes of sickness and health…. And because health and sickness and their causes are sometimes manifest and sometimes hidden, and not to be comprehended except by the study of symptoms, we must also study the symptoms of health and of disease” [34,35].
The English Roger Bacon maintained the scientific empiricism of the Greeks and described the scientific method as a repeating cycle of observation, hypothesis, experimentation, and the need for independent verification. He suggested that medicine should be based in remedies coming from chemistry. However, still the dominant philosophy of science was a religious version of the Aristotelian philosophy. The Black Death, a recurring outbreak of bubonic plague that began in 1347, disrupted the progress of science in Europe for more than two centuries [33]. It is interesting that before the discovery of America in 1492, China was the world technological superpower in discoveries and inventions [1]. The introduction of papermaking and printing reduced the gap between artisan and scholar classes. Then became the age-long recovery, the European Renaissance of humanism and learning, when concrete and abstract sciences, architecture and engineering, agronomy and medicine, were re-discovered from the Greeks [2]. Perhaps, future studies could discover the presumably antique “Hindu and/or Chinese scientific revolutions”, apart of the real technological ones.
2.2. Methodological Launching of the Scientific Medicine
2.2.1. Technological and Scientific Revolutions
Science, in its modern sense, came into being in the 16th and 17th centuries, with the merging of the craft tradition with scientific theory and the evolution of the scientific method. In the next 400 years, several technological and scientific revolutions with new scientific discoveries, inventions, and innovations produced great progress in medicine and in other sciences. The first revolution arose in the United Kingdom (UK), and later occurred in Continental Europe, United States of America (USA), Japan, and Russia. The once advanced India, China, Near/Middle East, Mexico and Peru, and the rest of the world stayed back [1,2].
In a post-positivist view, the scientific revolution began with the rejection of traditional paradigms: geocentric theory of the Greek Ptolemy for heliocentric theory of the Polish Copernicus. The Swiss Paracelsus rejected older alchemical and medical theories and found iatrochemistry and pharmacotherapy. The Belgium physician Andreas Vesalius, rejected earlier medical teachings with his dissections of human bodies in Italy, and with his anatomy, “Seven Books on the Structure of the Human Body” in 1543 helped to found modern medicine, surgery, and biology. The Italian physicists Galileo Galilee and others invented the telescope and established the science of mechanics. It was discovered the circulation of the blood pumped by the heart by the English physician-physiologist William Harvey who wrote “On the motion of the Heart and Blood” in 1628, and it was founded modern chemistry by Boyle. The Dutch van Leeuwenhoek invented the microscope, allowing the discovery of microorganisms and cells, and the beginnings of microbiology and cell biology. The Swedish Linnaeus began the scientific classification of 12,000 living plants and animals into a systematic arrangement. There was an improved communication of scientific knowledge by the rise of learned communities in European countries’ societies and academy of sciences in the 17th and 18th centuries, for the discussion and publication of scientific results [I,11,30-33].
In clinical medicine, after two centuries of delay of the recovery and restoration of the Hippocratic principles, the English Thomas Sydenham defined the nosological concept of disease in 1666-1683. The Italian Baglivi, and the Dutch Boerhaave, who with 12-bed ward taught many European physicians and even consulted in China, reoriented again the clinical method into the observation of the facts of the patient at the bedside correlating them with the autopsy findings, and then from this to its abstract elaborations on 1700. Afterwards, the Italian Giovanni Morgagni established morbid anatomy, or pathology, as a discipline with “The Seats and Causes of Diseases” in 1761, introducing the anatomical concept in medicine. The English Edward Jenner in 1796 founded scientifically vaccination with cowpox to immunize against smallpox, although Benjamin Jesty in 1774 first vaccinated his own family, and probably it was done in India and China a millennium ago too [I,31-32].
The interview and physical examination of the patient were enriched and unified with the percussion in 1760 and auscultation in 1816, by Auenbrugger and Skoda in Austria and Corvisart and Laennec in France, founding the modern clinical method of physical diagnosis. Laennec first sought and founded the confirmation of the clinical diagnosis at the autopsy table and united pathological anatomy and clinical medicine by an inseparable bond, and created a new technology to hear indirectly body sounds: the stethoscope. Afterwards, the macroscopic confirmation in the surgery and autopsy rooms became the microscopic verification by the histology developing the biopsy techniques. The urban migration in Europe in the late 1700s and early 1800s, coupled with the development of the French hospital system, made available to physicians a concentration of human illnesses never seen before [31-32]. In 1770, the Scottish John Brown wrote the last rationalist medical system “The Elements of Medicine” at the style of the Newtonian physics corpus of theory [36]. It was rejected as speculative by the European medical community until the early 19th century [37].
“An Inquiry into the Nature and Causes of the Wealth of Nations” published in 1776, by the British economist Adam Smith, stressed the advantages of division of labor and advocated the use of machinery to increase production. He urged governments to allow individuals to compete within a free market in order to produce fair prices and maximum social benefit. Smith’s work gave economics the stature of an independent subject of study and his theories greatly influenced the course of economic thought for two centuries re-blossoming again in the late 20th century [1,2]. The German economist Karl Marx produced “The Capital” in the 19th century, with the theories of struggle of social classes as engine of social development, and of the surplus value in capitalism. They inspired two socialist failed experiences, the Paris Commune in his times, and in some Eurasian and Southern countries the 20th century. His theory did not predict the untenable inefficiency of the central planning system, neither the possibility of capitalism to autocorrect itself, and made more humane and less unfair it [33].
In the 19th century, the German pathologist Rudolf Virchow, known as the father of scientific medicine, pioneered the development of pathology and scientific study of disease. He showed that all diseases result from disorders in cells, the basic units of body tissue. His doctrine that the cell is the seat of disease remains the cornerstone of modern medical science. Johannes Mueller in Germany laid the foundation for experimental laboratory science from 1830 until 1900. In order for clinical diagnosis to progress further, the causes and mechanisms of diseases had to be investigated. These investigations depended upon progress in the basic medical and biological sciences: biochemistry, pathology, physiology, experimental pathology, bacteriology, pharmacology. For the first time the causes of diseases were being explained. This allowed an epistemological shift of revolutionary proportions, and became clear that experimental methods could be applied to the study of disease, therapeutics, and health [I,30-33]. The discovery of the anesthetics effect of nitrous oxide by the US dentists Horace Wells and William Morton in 1844-46, was the essential prelude to modern surgery, followed by the introduction of muscle relaxants by the Canadian physician Harold Griffith in 1946. The origin of modern epidemiology was in 1854, when John Snow demonstrated the transmission of cholera by water from a contaminated well by analyzing disease rates among citizens served by the Broad Street Pump in London's Golden Square, arresting its further spread [I].
The theory of the English biologist Charles Darwin in “On the Origin of Species by Means of Natural Selection” in 1859, which said that evolution depends on random variations that permit adaptation to changing environments, is a milestone in the history of genetics. It laid the foundation for modern concepts of mutation and of how offspring differ from their forebears, and revived interest in the science of comparative anatomy and physiology. His theory was not accepted until the late 1880s by most biologists, and the English naturalist Alfred Wallace independently and simultaneously developed it. The plant-breeding experiments and treatise on the segregation of traits in peas of the Austrian biologist Gregor Mendel in 1865, although ignored until 1902, when William Bateson wrote Mendel’s Principles of Heredity, stimulated studies and laid the foundations of human genetics [I,16,33].
A milestone in medicine history occurred in 1870s when the French chemist Louis Pasteur and German physician Robert Koch, separately established the germ theory of disease. In the 1880s Pasteur, demolished the concept of spontaneous generation, discovered fermentation and pasteurization, and invented the anthrax vaccine and an anti-rabies virus serum. Koch first isolated anthrax, cholera, and tuberculosis bacteria in cultures, found modern scientific bacteriology, and created own causality postulates. In the development of this theory was important the pioneering work of the American physician Oliver Holmes and of the Hungarian obstetrician Ignaz Semmelweis, who showed that the high rate of mortality by puerperal fever in women after childbirth was attributable to infectious agents transmitted by unwashed hands after the performance of autopsies, and the application to surgery of the antiseptic principles of the English surgeon Joseph Lister [I,16,33].
It began the development of other precision instruments such as the kymograph by Ludwig in 1846, the ophthalmoscope by Helmholtz in 1850, the thermometer by Wunderlich in 1871, the reflex hammer by Erb and Westphal in 1875, the sphygmomanometer by Riva Rocci in 1896 with its precursors Hales in 1733 and Poiseuille in 1828. In 1895, Roentgen discovered the x-rays and in 1905, the Curie’s couple discovered the radioactive isotopes, which together with the ultrasound, opened radiology as the second great branch of macroscopic imaging technologies after the microscopic ones, which advanced again with the electron microscope in 1930s. The 19th century urine, blood and other fluids physical-chemistry analysis and cell count in the clinical laboratory, completed the first set of auxiliary technologies for screening, exclusion and confirmation diagnosis and prognosis of disease in the living patient [33].
Scientific immunology really began in 1890, when Emil Behring and Kitasato Shibasaburo developed their diphtheria antitoxin and, in the process, discovered the antibodies. Christian Eijkman showed that disease could be caused also by a dietary deficiency of substances now called vitamins. In 1909, Paul Ehrlich discovered a first bactericide to kill bacteria without killing the patient's cells. With the development of quantitative physical chemistry, it became possible to express the course of enzymatic reactions in mathematical terms by Leonor Michaelis and Maud Menten in 1913. Following the discovery of penicillin by Alexander Fleming in 1928, antibiotics joined medicine’s chemical armory, making the fight against bacterial infection almost a routine matter. The failure to prove that genes were composed of proteins spurred Oswald Avery to experiment and in 1944 found that genes were composed of deoxyribonucleic acid (DNA), not proteins. James Watson and British Francis Crick elucidated the double-helical structure of DNA founding molecular biology. Immunology re-flowered in the1950s, shifting the focus from serology to cells, with the clonal-selection theory [I,16].
Since the Greek Rufus’ method, there was no change in the clinical history-taking method until the French Martinet’s method in 1827. In the US Rochester’s school of medicine, Deutsch and Murphy introduced their “clinical interview method” of associative anamnesis, or associative exploration in 1954. There Morgan and Engel with their work “Clinical Method” began to taught and extend it to other schools in 1969. "History-taking" (or interviewing) does qualify as a scientific method; asking questions in order that physicians "know more exactly some of the things that concern the disease"; a suitable manner of patient response is "with a faithful memory"; verification by questioning relatives and friends, advises that the physician "find out precisely." Therein is captured the essence of science in the human realm of history-taking, a perspective disregarded in this era dominated by the biomedical model [31].
The clinical judgment scientific method for the daily practice of medicine in quality medical care is the same for the clinical medicine research. Really, a physician always begins clinical research and trial in an individual patient and progressively extends it to other patients. The difference is in the objective and tendency. In medical care, he uses its scientific method to know what is necessary to do for the benefit of that “particular” patient. In clinical research the physician, utilize the same method to do what is needed to know “in general” in an individual patient and others for the benefit of similar patients with the condition under enquiry [8].
During the 20th century, the plethora of discoveries changed scientific medicine completely, due to spectacular advances in nutrition, antibacterial and cancer chemotherapy, endocrinology, and immunology, and important technological and scientific breakthroughs in electronics, cybernetics, computers, and in applied sciences, molecular biology, and genetics. With the exception of cancer, attention is faced in morbidity rather than in mortality, and the emphasis has changed from keeping people alive to keeping people fit [11]. In the last 60 years, the need for autopsies had decreased, because it can be made virtually when the patient is alive with the new biochemical and biophysical high technologies, as the fiber optic computerized endoscopies even for minimum access surgery, computerized tomography of 64-slices, monoclonal antibodies for diagnostic and therapeutics, and so on
Now, the techno-scientific revolution is beginning in China and India, as free-market economy develops, and the progress is passing from the Atlantic Centuries to this new Pacific Century.
2.2.2. Scientific, Logical, and Philosophical Bases
The philosophical basis of the scientific revolution or invention of invention [2], were given by two main philosophers. The English empiricist Francis Bacon in the “New Organon” urged that the experimental method played the key role in the development of scientific theories. For these contributions, he is often thought as the “Father of the Modern Scientific Method”. He opened a new era where truth was sought from experience, not from authority. He introduced the important principle of establishing an inductive logic method of meticulously observing events [11,33]. It allowed basing clinical practice and research on a structured scientific method evidence-driven, which was suited to the improvement of scientific hypotheses [29].
The French rationalist Rene Descartes held that “the universe is a mechanical system that can be described in mathematical terms”. He developed the method of deductive reasoning, to account for observed phenomena based on clear and distinct ideas. He formulated in times when there were any empirical knowledge about electromagnetic phenomena and the function of the brain, a dualist concept separating the human mind from the body, considering the body “a purely passive machine driven by mechanical causality”. He thought that this theory would result in removing from medicine the ethical-religious taboos that were retarding it since millenniums ago, and would contribute to its scientific advance [11,33,38-40].
These advancements were enriched by the application of the hypothetical, analytic and deductive method of physics created by the English physicist-mathematician Isaac Newton for scientific research. He created a series of extraordinary breakthroughs, including new theories about the nature of light and gravitation, and the development of calculus. He changed how people viewed the universe and marked the birth of modern science. Newton’s work showed that nature was governed by basic rules that could be identified using the scientific method [33]. This new approach to nature liberated the 18th-century scientists from passively accepting the wisdom of the ancient Aristotle or medieval religious authorities as St. Thomas of Aquinas and others, which had never been tested by experiment. In what became known as the Age of Reason or of Enlightenment, scientists began actively to apply rational thought, careful observation, and experimentation to solve a variety of problems.
The German scientist and philosopher Kant tried to reconcile philosophically empiricism and rationalism by arguing that, knowledge itself comes from experience, and the mind uses reason to structure knowledge [33]. While the final rigorous formal scientific method of hypothesis-driven research was emerging from non-medical sciences, it was not until well into the late 19th century that medicine began to embrace this new approach [26,29].
The scientific method has evolved over many centuries and has now come to be described in terms of a well-recognized and well-defined series of steps. First, information, or data, is gathered by careful observation of the phenomenon being studied. Based on that information a preliminary generalization or hypothesis is formed, usually by inductive reasoning. This in turn leads by deductive logic to a number of implications that may be tested by further observations and experiments. If the conclusions drawn from the original hypothesis successfully meet all these tests, the hypothesis become accepted as a scientific theory or law; if additional facts are in disagreement with the hypothesis, it may be modified or discarded in favor of a new hypothesis, which is then subjected to further tests. Scientific hypotheses can be useful, just as hunches and intuition can be useful in everyday life. However, they can also be problematic because they tempt scientists, either deliberately or unconsciously, to favor data that support their ideas. Scientists generally take great care to avoid bias, but it remains an ever-present threat. Throughout the history of science, numerous researchers have fallen into this trap, either in the hope of self-advancement or because they firmly believe their ideas to be true. The ability to predict new facts or events is a key test of a scientific theory. On the other hand, when theories fail to provide suitable predictions, these failures may suggest new experiments and new explanations that may lead to new discoveries [26,33,41].
In the last 250 years, it was also developed in science though more slowly a synthetic, inductive and systemic method lastly from the evolutionary biology, information theory, and cybernetics, with an integrationist approach complementary to the differentiation approach [42-44].
2.3. From Reason and Dogma to Probability of Facts
At the end of the 18th century after the mathematical calculus of probability developments of the English Thomas Bayes, German Karl Gauss and French Jacob Bernoulli and Pierre Laplace (known as the “French Newton”), the latter explicitly cited medical therapy as a possible domain for applying the probability calculus. In the twilight of the Enlightenment and dawn of the French Revolution, this state was looking for a “science of man”, where the human individual could be characterized and the “human judgment” improved with mathematical precision. These times passed to history as of the Probabilistic Revolution [I,7].
Then medicine was departing of an excess of rationalism and dogmatism, reentering in the way of empiricism again in the fields of development of medical pathology, diagnosis, and therapy, when it did not have yet another scientific method apart of observation. One task was to support clinical judgment in decision-making in relation with the safety, efficacy and efficiency of the treatments that existed and were coming for the diseases that were being discovered and handled. Another task was to develop its scientific method and foundation.
In those times medicine was dragging the whole set of antique remedies and quackery of eight millenniums ago, together with the modern systems of quackery and the new treatments without a solid base on evidence. Clinical judgment method was analyzed as an “amorphous concept” and its results as a form of “tacit knowledge”, by mathematicians trying to formalize medicine as the other sciences. Clinical science quantification was seen through the calculus of probability, because there was the idea that medicine could never become a determinist science as physics. The French physicians Pierre Louis, with his clinical “numerical method”, telling that the physicians could become scientists without leaving the clinics --to go to the laboratory; and Jules Navarret, firstly engineer, applying probability calculus to medical pathology, diagnosis, and therapy, were crucial to fill these practical scientific needs [7].
Louis, called first full-time clinical investigator, synthesized the previous developments and put physical diagnosis on a secure footing at the bedside and autopsy room in the period 1800-1850. He used to list each case in numerical order and compared the group receiving a certain therapy against the group that did not. Thus, he demonstrated that bloodletting was of uncertain value in treating typhoid fever and other diseases. There were many critics of his "numerical method” Louis' reply was that "in the difference between exactitude and vagueness, lies the difference between truth and error” [7,31]. Navarret, wrote a manual on “General Principles of Medical Statistics”, following the views of Laplace and of Simeon Poisson --discoverer of the “law of large numbers”. Navarret applied probabilities to clinical statistics, seeing the science of medicine as an extension of this mathematical theory [7].
In these times, the French astronomer-mathematician Adolph Quetelet was developing other application of the probability calculus: the “average man” of a country, as the central idea of “gravity” in physics, with a social orientation named “social physics” [7]. It found extensive use in clinical research and practice in the range of normal or healthy values of parameters [20].
There were heated debates in the Parisian Academies of Science and Medicine, at this time many physicians who did not think that in clinical medicine could be applied any kind of mathematics, including probability, while others accepted it. Among the first ones, was the French Pierre Cabanis, who thought that medicine was more art than science, and was skeptic and fearing that quantitative approach would be a distraction. Francois Double discussed surgical trials results of a bloodless lithotrity to remove bladder stones created and investigated by the surgeons Ulrich Trohler and Jean Civile with a similar method to Louis. Double rejected to convert clinicians in scientists through the use of “aggregative thinking” and “quantification”, with emphasis in a group, instead of the individual patient, interfering with the sense of humanitarian ethos. He stated that the eminently proper method in the progress of medical science diagnosis was logical analysis and not numerical analysis. The engineer Claude Navier conceded to Double, that results could be determined by experience and induction, but that this inductive method could be improved by the probability calculus in the necessary rigor and exactitude. Doube wrote: “Why is the science of man still so far from the physical sciences on which proposals have been made to model it without ceasing?... It is because there is no similarity. In the physical sciences, the observation produced is always the same; in the human sciences, it varies without ceasing. It is this prodigious variation that created difficulties in the physiological sciences”. Double expressed about Quetelet and Poisson attempts of mathematization of medicine, that “since the men of mathematical certainty dispute among themselves, the physicians also tolerate not being in agreement… The matter is that doctors embrace have more serious importance that the matters which the geometers occupy themselves…. Both the construct of an average man and a law of large numbers, shift attention from the individual needing treatment to the population of the sick people as a whole”. Even Louis attempted to distance his numerical analysis to convert medicine in an empirical science from these views of all such mathematically trained [7].
The French physician Benigno Risueño d’Amador stated that the principle concern of the physician should be healing the individual sick person, taking into account its subjective impressions too. The focus in the individual patient was not only a matter of intellectual predilection but also of professional ethic. Risueño d’Amador cited arguments of political economists Smith and Say, who had declared, “statistical results were too uncertain because they merely told of results at a particular instant in time for particular individuals. Generalization of the results to future cases was impossible because the uniqueness of the individuals involved”. Echoing (and rebutting) Laplace, Risueño d’Amador declared: The calculus of probabilities has been call good sense reduced to a calculus, but…. one can perhaps ask whether good sense is calculable the same as intelligence, passions, human affections, and all which pertains to moral and intellectual life and affects human beings [7].
On this matter, the German ophthalmologist Julius Hirschberg said that one thing was quite evident, that such statistical methods would give the deathblow to most of our modern systems of quackery. The German physician Friedrich Martius stated that the real progress of medicine that which sheds light on causal relationships of phenomena, lies in experimental induction, not in the numerical method. The Scottish physician William Alison argued that statistical results may often prove useful in determining therapy even if the scientific reasons underlying the therapy’s efficacy remains unknown [7].
It was accepted by everybody that medicine cannot has the determinism of physics, chemistry, and other sciences, until appeared the French physician-physiologist Claude Bernard, defending the experimental medicine and developing its theory of scientific determinism [11]. Francoise Magendie convinced him to look to the laboratory as a way of creating a science of medicine autonomous from both clinical practice and government regulation. Bernard told that for the laws of medicine to become scientific, they could be based only on certainty, on absolute determinism, not on probability. To base medicine only on empirical observations and statistics, as Louis had done in the clinic, would be to assume that medicine was merely a passive observational and conjectural science rather than an interventionist experimental one. He stated that the “logic of facts” and the carefully planned experiment controlling the conditions of the living organisms in the laboratory was the key to providing medicine with a scientific foundation [7]. He pointed out the difference between the observational and experimental methods and physicians, in his “Introduction to the Study of Experimental Medicine”. His determinist system dominated applied science and medicine until the beginning of the 20th century [11].
The German clinician Karl Wunderlich advocated for the view that precision measuring instruments as the thermometer, would confer objectivity on medical observation in the realm of diagnosis. He said, “a science of medicine like other sciences must depend upon the classification of facts, upon the comparison of cases alike in many respects, but differing somewhat either in their phenomena or in the environment. The great obstacle to the development of a science of medicine is the difficulty in ascertaining what cases are sufficiently similar to be comparable, which difficulty is in its turn largely due to insufficient and erroneous records of the phenomena observed. The defect in the records is largely due, to ignorance on the part of the observers; to the want of proper means for precisely recording the phenomena; and to the confused and faulty condition of our nomenclature and nosological classifications” [7].
In Britain the physician and statistician Francis Galton after been inspired by Charles Darwin’s evolutionist theory, created the statistical correlation, the science he termed Eugenics, and founded the modern statistical theory. He studied the distributions and deviations from the mean of hereditary traits to improve human species through a process of controlled breeding. Studying the hereditary genius, he discovered the reversion (regression) toward mediocrity in successive generations as a mathematical consequence of the Gaussian curve law of errors. He wrote “Hereditary Genius”. Where Quetelet made biological averages into something real, Galton now added another tier to that reality; he had made correlations as real as causes. Galton created the first eugenics laboratory and biometric laboratory with the mathematician Karl Pearson, and freed him from the prejudice that sound mathematics could only be applied to natural phenomena under the category of causation. Both created the Biometrika journal in 1901 [7].
In the realm of therapy, the laboratory-based techniques of microbiology were seen as a key to providing medical treatment scientific basis. The last great debates were between the microbiologists and statisticians. Bacteriology offered the prestige of laboratory science in the diagnosis and treatment of disease. Statistics in turn, offered the prestige of number and quantification in proving the efficacy of results. Then became a triangular demarcation between the clinician at the bedside, bacteriologist, and statistician over who should remain the final arbiter of medical knowledge [7]. It is interesting that in physics, chemistry and other sciences, the same community of scientists were the arbiters of their own results. In these times, statistical techniques were still associated more with social analysis than with pure scientific research. Galton and Pearson had two important physician followers: the American Raymond Pearl, and the British Major Greenwood, who dedicate both to medical statistics.
The British bacteriologist and pathologist Almroth Wright had two important debates with the statisticians. One was due to his results with an anti-typhoid inoculation and the other due to his results with the opsonic index of response of the patient to infection. As an arbiter, Pearson determined mathematically the correlation coefficient of Wright’s results between immunity and inoculation, mortality and inoculation. Due to the significant low coefficient of correlation intensity, Pearson declared that it would justify suspension of the operation as a routine method and advocated further study of the issue. Then, in his vaccine therapy research, Wright created the opsonic index. This was a ratio with values around 1 (from 0.8 to 1.2) between the numbers of bacteria found in 25 to 100 leukocytes of a patient with infection (in which it was increased) and of a normal person. Wright hoped to revolutionize medical therapy with these results to detect sub-clinical infections before symptoms appeared. However, as arbiter Pearson and Greenwood found that the distribution of the opsonic index values was asymmetric and skew and the various statistical tests based on the assumption of a normal distribution and the use of means could not be readily applied. Wright and Greenwood held that medical research ought to be predicated on a scientific methodology rather than merely clinical judgment; however, they disagree if this was the statistical experiment with correlation or the crucial experiment with laboratory-based experimentation [7].
Pearson maintained the Galton’s eugenics project until he could, but he lacked the necessary physiological thought to have success with it. Eugenics was based on the Darwin’s theory, but Darwin shown an antipathy toward the use of statistical arguments, being his work not available as a locus classicus to justify statistical methodology. Pearson offered the project to Greenwood, but he was more interested in the application of statistical methodology to clinical medicine and epidemiology, and finally the eugenic laboratory was closed. Pearl make this absolute, stating that “there is no inherent reason why medicine in every one of its phases should not become in respect of its methods an exact science, in the same sense that physics, chemistry, or astronomy are to-day exact sciences. That this goal will be reached in exact ratio to the extent to which quantitative methods of thought and actions were made an integral part of work of every sort of medicine. That no number or figure can be said to have any final scientific validity or meaning until we know its probable error, being this the measure of the extent to which the number will vary in its value as the result of chance alone” [7].
Greenwood and Pearl created in the London Institute of Hygiene and Public Health School of John Hopkins the experimental epidemiology. Ronald Fisher in his “Design of Experiments” in agronomy of 1935 put forward the central importance of randomization. He created the analysis of variance and the multivariate analysis. The English physician-statistician Austin Bradford Hill with the Galton, Pearson, Fisher, Pearl, and Greenwood, developments wrote his “Principles of Medical Statistics” in 1937, and made in 1946 the first randomized controlled and double-blind clinical trial of streptomycin versus rest in pulmonary tuberculosis. Afterwards, began the statistical design and analysis in epidemiology with the English Richard Doll’s studies of smoking and cancer in British physicians. In 1962 after the public protest for the German thalidomide adverse secondary effects, the US Food and Drug Administration (FDA) regulated the evaluation of the new therapies with randomized controlled double-blind clinical trials, beginning in the National Institutes of Health, arriving to the western democracies in the 1970s and socialist countries in the late 1970s.
In the last five decades, the American and English physicians Alvan Feinstein and David Sackett have published a thousand papers, condensed in more than a dozen of books in clinical judgment, clinical biostatistics, clinimetrics, and clinical epidemiology. With them they have tried to adjust the medical and health care requirements from the clinical judgment scientific method with the auxiliary statistical techniques, while there have been a movement to the extreme of the pendulum towards mathematical elaborations instead than to clinical medicine science needs, searching for the just medium, in benefit of the high quality caring of the individual patient and population of patients scientifically and humanitarianly [20,22,45-48].
3. Advancement of the Scientific Method in Medicine
3.1. Inharmonious and Disproportionate Progress of Medical Sciences
The British general practitioner le Fanu has told that clinical medicine science and research today, from the perspective of general clinical medicine specialties especially in primary care, has lost the excitement that accompanied the explosion in treatments after the Second World War II, and has certainly changed beyond recognition. He described four paradoxes: 1. Crisis of family physician services displaced by hospital services; 2. Crisis of family physician services overburdened by preventive services; 3. Rediscovery of homely remedies by traditional practitioners when family physician abandoned them for scientific medicine; and 4. The widening gulf between achievement and advancement, given by the magnitude of the increased funds allocated to health (and research) which, for instance, in Britain have doubled in the last ten years from £23 billion to £45 billion, without there being any measurable or subjective impression of improvements to justify such an increase. He continues: “between 1945 and 1975, virtually the most significant medical developments occurred, and further advances of such magnitude probably will not continue to accrue. There were "twelve definitive moments" of medical discovery, invention and innovation: penicillin (trial), cortisone, streptomycin, chlorpromazine, intensive care, open-heart surgery, hip replacement, kidney transplants, the control of hypertension (and stroke prevention), the increased survival of childhood cancer, "test tube" babies, and the clinical importance of helicobacter pylori. Of these, the discovery of antibiotics, cortisone and the importance of helicobacter are what Lewis Thomas in his Lives of the Cell designated high technology, and the other eight half way-technology: a level of technology that is, by its nature, at the same time highly sophisticated and profoundly primitive. It is the kind of thing that one must continue to do until there is a genuine understanding of the mechanisms involved in disease. Post war medicine also developed treatment to control the progress of Parkinson’s, rheumatoid arthritis, and schizophrenia. For 30 years clinical science, medical technology and pharmaceutical innovation thrived. Them abruptly, the vigorous march of modern medicine forward flagged, and for the past 25 years research that have focused on discovering cure and developing vaccines has found itself hobbled by social theories of medicine and political debates about health care. Further medical breakthroughs in areas like transplant technologies and the new genetics, meanwhile have become swamped in ethical issues. It is the clinical science necessary for the development of half way-technology what is disappearing. The era of large-scale physiological research in patients is largely over. One need only observe all the medical departments engaged in molecular biology rather than in bedside research [49].
In the other hand, in global health, genomics has emerged as one of the means that can be used to address huge health problems and other challenges in developing countries. The realization of this potential, however, depends on a diverse set of policy measures aimed at translating scientific discoveries into goods and services. These technologies include: molecular diagnostics; recombinant vaccines; vaccine and drug delivery; bioremediation (use of living organisms to degrade hazardous matter); sequencing pathogen genomes; female-controlled protection against sexually transmitted infections; bioinformatics; nutritionally enriched genetically modified crops; recombinant therapeutic proteins; and combinatorial chemistry [51].
Nevertheless, five years after publication of two drafts of the human genome, the American Maynard Olson finds himself longing for another "lurch." To be sure, genomic scientists across the world have chalked up many achievements since 2001, but, like many of his colleagues, Olson is feeling more impatient than celebratory. Progress has included a blizzard of comparisons between the human sequence and many others, including the chicken, the mouse, the rat, the dog, and the chimp. The flourishing of comparative genomics, says Olson, has changed the focus of genomics from a single reference sequence of genes to a rich variety of "functional elements," largely sequences that serve as ignition switches, brakes and accelerators for gene expression. And the focus on single-base changes has widened to an array of evolutionary rearrangements: insertions, deletions, reversals, and duplications. There are new tools: new global databases of all functional elements in genomes (e.g., ENCODE), small molecules for chemical genomics (e.g., PubChem), and a raft of protein structures. And yet the last five years, in Olson's view, have been "a period of a great grinding of gears, kind of shifting of gears." In the terms of the science historian Thomas Kuhn, it has been "a period of consolidation and more normal science." Others, such as Sydney Brenner of the Salk Institute, and Nobel Prize…. go further, worrying that the genome sequence and the growing lists of sequences and proteins and protein interactions and functional elements don't get very deep into such core problems of biology as the operations of the cell, of development from egg to adult, or the problem of consciousness. "We've become very geno-centric," says Brenner. "The cell must become the focus." What vexes many thousands of colleagues around the world most is that genomics hasn't yet moved into the "real world" of medical relevance” [52].
Besides this advancement due to the power of the scientific method in extending the boundaries of biomedical knowledge and technologies, however, general and family medicine more bio-psychosocial medical research have been let back, by the high complexity of their medical general problems, and more than all by the lack of a suitable scientific training of most of their own physicians. Unfortunately, the scientific advancement of general clinical medicine in secondary and most of all in primary health care levels is not only dependent of the development of electronic-primary care research network to link physicians and their patients with researchers conducting clinical trials in the tertiary care level, providing cutting-edge technology along with training, and re-engineering clinical research [53], and it cannot be achieved only promoting primary care practice-based research networks, working at the interface scientific level between present academic research and quality improvement search [54].
Even in the poor developing countries, the medical care challenges has arrived to the desperate point to make necessary a clinical economic approach --from health and education to agriculture and critical infrastructure-- one isolated rural village (or urban slum) at a time, working with the civil society, and bypassing misruled governments if necessary [1]. In these countries in the future, the shift of paradigm that would be necessary would be greater than in most developed countries. It would be from the biomedical to the new bioeconomic-psychosocial paradigm [55], over the necessary but not sufficient clinical social medicine and epidemiology approaches [56], to complement all the known scientific approaches and paradigms until today.
3.2. Logical and Methodological Problems of Clinical Medicine Sciences
Modernly medical sciences can be divided as in the times of the Greeks into three main branches too. The clinical medical-surgical sciences, which are the trunk or primary branch, and the laboratory and health sciences the two derived branches. They correspond to the clinical and experimental medical practices and public health activities. There is a consensus in reference to the colossal amount of fragmentary results of investigations on disease achieved in the last two centuries, but specially by the western medical and health sub-disciplines in the last 60 years [14,16,II,28]. Besides, few attempts of thorough outcomes but still very rudimentary, continue being sustained only by the eastern medical disciplines.
There are many partial theories about different dysfunctions, diseases, and disabilities, even for aging and dying. Their causes, well known by doctors, are not well understood by the patients, who need to be more aware of the procedures for their protection, diagnosis, palliation or cure, if possible [14]. There are few integral scientific theories about function, health and survival with good quality of life of the person, family, and community. Still the health causal webs have to be discovered as well as better means to promote, diagnose and recover health, credible by the physicians and by the individuals they take care of [III,IV]. Today, basic and applied --technological and non-technological-- research fields of scientific medicine, make up a mosaic of more than one hundred academic disciplines with a tendency to increase. Clinical medicine specialties work along with art and engineering in the same way as other practical sciences of particulars [57], but simultaneously, they as sciences of generals, become more complex than experimental biomedicine and public health, an even than agronomy and economics do.
This is due to the abundance of clinical, physiological, and pathological observations and confirmations in surveys and trials, with all their biases not entirely controlled yet, even using placebo, elaborated blind and randomized statistical designs, analyses, and meta-analyses, powerful computers and information high technologies due to the hidden variables [58,59]. The statistical hypotheses beside the best software, at their empirical cognitive level, cannot reach yet the rational level required to create, formulate and prove even the partial scientific hypotheses and "laws" completely. Theory and practice of the traditional oriental and Arab medicine, with western complementary, alternative, and holistic medicine practice, which tend to be more integrative intrinsically, have been poorly studied and tested along with modern sciences, weakening the possibility to unify a thorough body of medical scientific knowledge.
When the results in the multi-causality field of diseases are revised, there are still doubts about the accuracy, order and integrity of some causal chains or mosaics about simultaneous nosological entities, which explain part of the still limited control achieved over them [58]. For instance: Hypertension, Is cause or effect of atherosclerosis, or both are effects of unknown causes [60]? What relationships exist between the traditional risk factors of coronary artery disease, including C-reactive protein and the new homocysteine and chlamydia pneumoniae factors [61]? In atherosclerosis and cancer research, the old inflammation theory has been re-studied in the last two decades [62,63]. Is helicobacter pylori, the real cause of so many "degenerative diseases" [64]? Is HIV a cause or an opportunistic infection in patients with AIDS due to other causes [65]? Are the biophysical and biochemical abnormalities in the brain of the schizophrenic or depressed patient, all causes, or some are partly consequences of other causes? Are the social contexts and psychological alterations in patients’ behavior, all manifestations, or some belong to their causes, and interact with other environmental and genetic conditions [40,66]?
There are also hesitations regarding the efficacy and even certain damages of some diagnostic, therapeutic and protective means used to deal with some diseases. For example: Surgical treatment is not always effective because of the systemic nature of some cancers when first diagnosed [67]. Excessive radiation and chemotherapy may accelerate the death of the fragile elder cancer patient [68]. Radical prostatectomy and external beam radiotherapy have not been conclusively better in quality of life than has been watchful waiting for the treatment of men with localized prostatic carcinoma. Prolonged survival is not ultimate proof of the effectiveness of early detection by screening for prostate cancer, because, screening picks up proportionately many cases of slowly progressing disease [21] --or stabilizing or regressing disease. There is an increase in asthma patients and deaths, in spite of the development of new elaborated preventive and therapeutic measures --vaccines and drugs [69].
Besides, research on linear and nonlinear causal relationships of different health states or entities still have to do much more. Is cancer a physiological mechanism of natural selection, once genome deterioration is sensed [70]? Is asymptomatic atherosclerosis really a disease in the advanced elderly [71]? Is the structural progression-stabilization-regression process of atherosclerotic plaques, a physiological and/or patho-physiological process? Has this microscopic process nonlinear relation with the macroscopic functional manifestations and responses to the long-term pro-health lifestyle, lipid-lowering and antihypertensive methods? Which are healthy lipoprotein patterns? Are high-risk blood cholesterol levels (more than 5.1 mmol/L) associated to more atherosclerotic patients and deaths [71], whereas low concentrations achieved by therapy (less than 3.9 mmol/L) are related to more deaths by cancer, suicide, violence, among other causes [72]? "Positive" or direct health causes as well as the means to help strengthen their actions, have to be investigated from inside a more comprehensive notion of health [III,IV], and also from an outside stand point, closer to non medical concepts of the persons and public officials [73].
Human suffering, well being, health and life, do not have so many conceptual networks, models and methodological research, to describe, explain and predict them, as do disease and death [III,IV,66]. There is lacking a unique doctrine of scientific medical and health general theory integrating and focusing all of them in the whole individual [74] and in the population [14,16,75-77]. Suffering is still neither well understood nor handled [14,57,66]. Currently, individual health is still seen as a physiological state (without disease) where each known clinical parameter value is within its normal range or interval, less as a state of minimal happiness felt when the vital goals are achieved by second-order abilities, in standard circumstances [14,16,III,IV,75]. Population health is still perceived mainly as a social state with low indexes of mortality, morbidity, and disability, by age and sex [13,14,16]. Up-to-now, “health status” is still a unique and integral "well-being state or ideal model", not well described yet, and opposite to thousands of partial diseases well described.
Few medical and health theories integrate the complex systems of cognitive levels that interact within and also with the main object of that general medical and health sciences, which is not only the organic molecule, human gene, cell, "meme", and consciousness, within a social organism, but also the healthy and sick individual as a whole-system [66,74,78,79]. Frequently, the biological, psychological, anthropological, sociological and economic theories are excluded among them or included as secondary or tertiary theories in the scientific explanations.
ME QUEDE AQUI
3.3. Restoration of the Old Natural and Traditional Clinical Medicine
The restoration of old patient-centered care with old alternative or complementary medicine (CAM) by non-physicians practitioners when clinical physicians abandoned homely remedies for scientific medicine, more in the last decades is a concerning matter. In the last 60 years, scientific medicine has become very specialized by human subsystems and medical care technology-centered [49]. Clinical physicians could recover homely remedies such as massage, manipulation, dietary advice, and others. However, this is a complex problem.
Here it must be examined the impact of the unique and standard medical scientific method developed until now, in its applications of what has been called the oldest eastern and newer western schools of medicine. The oldest oriental medicine is in great part still delayed in a proto-scientific phase trying difficultly in the last decades with the current scientific method of physics --recognized as universal-- to undertake the entire richness of the essential body-mind unit of the human patient, and to become accepted as scientific being coherent with the predominant universal western sense of science. The youngest western medicine has hasty successfully progressed in parallel with that same analytical and hypothetical-deductive method of physics in the last 200 years, on the scientific study mostly of the patient’s body. This western medicine approaches the body-mind unit solely through only the hard observable facts or empirical evidences of the body, utilizing the material and energy high-technologies of diagnosis and treatment. However, it has been letting so far the soft unobservable facts or subjective “evidences” at the standard empirical level of knowledge of the patient desires, feelings, and responses, aside in a “scientific limbo level” until today. It is possible that these needs of clinical medicine and science could be solved through the combination of the material-energy with the relational information and communication high-technologies to continue forward in the future scientific medicine progress, but in the meanwhile the re-focus of the individual patient and family as a whole is a practical felt need.
The real logical inconsistency of western scientific medicine could be resumed with at least the reasons as follow: First, the insufficient possibilities of the physics scientific method by the moment to sense directly or indirectly the facts of the mind or “spiritual” domain, because of a paradoxical vacuum of the physical science and technological instruments to measure so far that relational informational and communicational human domain yet. Second, it is also due to the difficulties by the moment to validate as scientific and integrate with the physical scientific method the standard psychological and social analytical scientific methods. Third, it is additionally because of the ethical hurdles to make human experimentation and insufficient development of the human bio-psychosocial computer simulation. For these reasons, have been let relatively aside the integrated study of the “evidences” of the mind to be able to progress forward partially with the evidences of the body which are so far more consolidated.
There is a position toward integration on the matter, but with methodological hurdles. It is as follows: “CAM therapies are increasingly used by cancer patients for palliative and post-cancer preventive and/or wellness care. It is critical that evidence-based models be employed to both provide information for patients' use and informed consent and for physicians to advise patients and assess relative risk-benefit ratios of using specific CAM approaches within the cancer care paradigm. Research models for biomedicine have been somewhat limited when applied to broader, more holistic conceptualizations of health common to many forms of CAM. Thus, while numerous challenges to studying CAM exist a fundamental question is not just what CAM practices should be studied but how CAM should be studied. The authors propose a model that emphasizes methodological rigor yet approaches CAM research according to relative levels of evidence, meaning, and context, ranging from experimental, quantitative studies of mechanism to qualitative, observational studies of noetic/salutogenic variables. Responsibility for training researchers prepared to meet such challenges rests on both CAM and mainstream academic institutions, and care must be taken to avoid philosophical and practical pitfalls that might befall a myopic perspective of integration” [80].
There are emphatic criteria against integration, adducing that scientific medicine has never let out the study of the mind, and that most CAM successes have been due no more than to the placebo effect. For instance: “Before scientific medicine interfered with traditional practice, few folks lived to be as old as the youngest United States senator. Nor can the sorry public health statistics of our inner cities be attributed to inadequate access to folk remedies or group meditation. To paraphrase Lincoln Steffens: we have seen the future of unconventional medical practices and they do not work. Meanwhile, in the most important aspect of medical practice, the public health, young doctors are sweating over research grants that remain unfunded because an alliance of homeopaths and “New Age (of Aquarium)” (of Unreason) toe ticklers seems to have gotten hold of a dotty senator or two. As for those multicentered large-scale trials to be planned by the NHI Office of Unconventional Medicine Practices, one might direct the Ayurvedic, Taoist, and other CAM practitioners to the morbidity and mortality tables of rural Africa, India, and China today, the church records of Salem, Massachusetts of 1693, the life expectancy of Parisians in 1788, or even the bills of mortality of Cambridge, Massachusetts, on 1891” [3-6].
“William James, the finest writer even to have come out of the Harvard Medical School, believed at the end of his century what the new age healers believe at the end of our own: that the “thunderbolt has fallen and that the orthodox belief in reductionist science has not only had its presumptions weakened, but the truth itself [has been] decisively overthrown”. Well, not really. Reductionist science in James’s own field of medicine and physiology has had a decent run since its “overthrown” by the Boston psychics. The sanitary revolution of Lowell’s time was followed by the bacteriologic revolution of James’s, and this in turn was succeeded by the biological revolution of our days, which I used to call the flowering of DNA. The results are easy to quantify: In 1920, at the end of the bacteriologic revolution—and before the discovery of antibiotics—the average life expectancy in the United States was 33.6 years for males and 54.6 for females. By 1990, the life expectancy of males had increased to 71.8 and females to 78.8. There is no evidence that between 1920 and 1990 intervention from the spirit world had increased, or --James and the spiritualists to the contrary-- that the “truth itself” has been decisively overthrown” [4,6]. “Postmodernism --embodied in deconstruction, among other doctrines-- takes relativistic cultural analysis one step further. Value-free cross-cultural analysis states that science has validity within the community accepting its point of view, without necessarily being more valid than pseudoscience. Each position supposedly has its own criteria. Postmodernism, as I understand it, posits that there is not necessarily any validity at all to the scientific view, which is taken to represent the prejudices of a system dominated by European males!” [6].
It is very interesting the opposition in our times between eastern and western medicine, in the issue that the first has not found yet a strong evidence for a different worldwide-accepted etio-pathogenesis, prevention and therapeutics. To eliminate this opposition, would be good to re-examine and re-describe the proto-scientific methods used by the Hindus and Chinese medicine schools, although they would be perhaps in some way different from the western medicine one. To integrate the achievements of the eastern medicine to the western ones in a universal body of medicine theories, remedies, and techniques, all scientific methods should be openly discussed, and must be agreement in the design of the trials and of the research.
In the history of the scientific method in medicine, some proto-scientific systems, as for example, of the Greek Cnidian and Galen schools, Arab Avicenna, and Scottish John Brown, were sanctioned as rationalist and speculative, because they could not convinced the medical community of the consistence of their systems in regards to the scientific standard evidences. It is not new that non-oriental and even European systems have been discarded in Europe before.
In the future, eastern and western scientists would have to study and work to legitimate the proto-scientific methods used by the Ayurveda, Taoist and other serious eastern schools of medicine, until now considered “pre-scientific” by the western medical scientific community. It must be found a way for an integration by both big schools, regarding to their bodies of knowledge, experiences, techniques, and technologies, and to their original scientific methods of demonstration of the scientific truth in medicine. In human clinical medicine must be conciliated in the future the fields of the objective fact, the subjective feeling, and the reason.
4. Methodological Complexities: Some Controversial Case Studies
Here it will be summarized three very controversial cases of medicine research projects and programs, which show why the scientific method is indispensable for medicine progress; how the scientific method allows the progress of new more accurate knowledge and efficient technology, but will show also some present methodological difficulties in the scientific research in medicine.
4.1. Case I: Oxygen as a Cause of Blindness in Premature Infants.
Jacobson and Feinstein [82], explains as follows the results of a clinical epidemiological research autopsy to determine the errors of more than a decade --1942 to 1954-- to end an iatrogenic epidemic in which high-dose oxygen therapy led to retrolental fibroplasia (RLF) in premature infants, blinding about 10,000 of them. The autopsy revealed a museum of diverse intellectual pathology. When first noted, RLF was regarded as neither a new disease nor a postnatal effect. In early investigations, the ophthalmologists did not establish explicit criteria for diagnosis and confused RLF with malformations previously seen in full-term infants. Because the patients were not referred until months after birth, the ophthalmologists assumed that the lesion, which resembled an embryologic structure, must have occurred prenatally. Other events suggesting a prenatal cause for RLF were its strong statistical associations with fetal anomalies, multiple gestations, and maternal infections. Although these events were also associated with prematurity, it was ignored when the RLF cases were compared with controls who were mainly full-term infants.
The postnatal timing of RLF was eventually recognized when investigators did cohort studies in premature infants and found that RLF could develop in eyes that were normal at birth. As the search for a cause turned to events occurring after birth, statistical associations were produced for agents such as light, vitamins, iron, vitamin E deficiency, and hypoadrenalism. Each study had its own methodological flaws: controls were missing for light; co-maneuvers were ignored for vitamins and iron; objective diagnosis was not used for vitamin E deficiency; and the research on hypoadrenalism contained biases in susceptibility and detection as well as problems of a competing outcome event. When the role of oxygen administration was first considered, the statistical association with RLF was stronger for vitamin- and iron-therapy than for oxygen. In addition, many investigators were dissuaded by contradictory evidence from institutions in which RLF was either absent despite high-dose oxygen or persistent despite reduced dosage. The contradictory evidence was later regarded as erroneous because of unsatisfactory delivery systems for the oxygen or failure to check the actual oxygen concentrations. An alternative explanatory hypothesis, rejecting the role of high-dose and long-duration oxygen, was the idea that RLF was due to "relative hypoxia", produced by overly rapid weaning from oxygen therapy rather than the duration of oxygen treatment itself.
In this case, the discussions finished long ago.
4.2. Case II: The Chemical Bases of the Various AIDS Epidemics
Duesberg, Koehnlein, and Rasnick [83], explain as follows the last 25-year record of the AIDS research. In 1981 a new epidemic of about two-dozen heterogeneous diseases began to strike non-randomly growing numbers of male homosexuals and mostly male intravenous drug users in the US and Europe. Assuming immunodeficiency as the common denominator the US Centers for Disease Control (CDC) termed the epidemic, AIDS, for acquired immunodeficiency syndrome. From 1981-1984 leading researchers including those from the CDC proposed that recreational drug use was the cause of AIDS, because of exact correlations and of drug-specific diseases.
However, in 1984 US government researchers proposed that a virus, now termed human immunodeficiency virus (HIV), is the cause of the non-random epidemics of the US and Europe but also of a new, sexually random epidemic in Africa. The virus-AIDS hypothesis was instantly accepted, but it is burdened with numerous paradoxes, none of which could be resolved by 2003: Why is there no HIV in most AIDS patients, only antibodies against it? Why would HIV take 10 years from infection to AIDS? Why is AIDS not self-limiting via antiviral immunity? Why is there no vaccine against AIDS? Why is AIDS in the US and Europe not random like other viral epidemics? Why did AIDS not rise and then decline exponentially owing to antiviral immunity like all other viral epidemics? Why is AIDS not contagious? Why would only HIV carriers get AIDS who use either recreational or anti-HIV drugs or are subject to malnutrition? Why is the mortality of HIV-antibody-positives treated with anti-HIV drugs 7-9%, but that of all (mostly untreated) HIV-positives globally is only 1.4%?
Here we propose that AIDS is a collection of chemical epidemics, caused by recreational drugs, anti-HIV drugs, and malnutrition. According to this hypothesis, AIDS is not contagious, not immunogenic, not treatable by vaccines or antiviral drugs, and HIV is just a passenger virus. The hypothesis explains why AIDS epidemics strike non-randomly if caused by drugs and randomly if caused by malnutrition, why they manifest in drug- and malnutrition-specific diseases, and why they are not self-limiting via anti-viral immunity. The hypothesis predicts AIDS prevention by adequate nutrition and abstaining from drugs, and even cures by treating AIDS diseases with proven medications. In this case, the very interesting controversy has about 20 years and still continues.
4.3. Case III: Rethinking Clinical Proteomics after Setback.
Constans comments [84] as follows are on “after a setback, biomarker researchers continue to debate the use of mass spectrometry in diagnostics.” For a while, it looked as if proteomics' next frontier was the clinic, if one was to believe the hype surrounding a 2002 study from US FDA and National Cancer Institute (NCI) team of scientists. It used mass spectrometry and pattern-recognition software to probe serum samples for ovarian cancer biomarkers. Their findings suggested that proteomic patterns --series of peaks in mass spectra representing unidentified peptides or low molecular-weight protein fragments-- could be used to diagnose early ovarian cancer with surprising accuracy. This was the hope in late 2003 when biotech startup Correlogic licensed Quest Diagnostics and LabCorp to market OvaCheck, a blood test for ovarian cancer based on the initially promising findings. But doubts about the validity of the criticized team’s results and the robustness of serum proteomics as a tool for biomarker discovery quickly emerged: a bioinformatician at MD Anderson Cancer Center (ACC), attempted to reproduce the results using FDA/NCI team’s own raw datasets and failed. He concluded that problems with data collection and processing made the diagnostic patterns found in the Lancet (journal) paper suspect unleashed a continuing debate about how to use mass spectrometry to uncover signatures of disease. Ultimately, the FDA announced in mid-2004 that Correlogic could not market OvaCheck until it published clinical evidence that the test actually worked in patients.
Since then, the proteomics community has reevaluated mass spectrometry as a diagnostic or biomarker-discovery tool, debating validation requirements and assessing the amount of information needed for diagnosis, and developing new instrumentation and techniques to make the method more amenable to biomarker discovery and clinical applications. The bottom line: proteomics' next frontier is the clinic. But it might take a little longer to get there. Summarizing, there were three problematic issues:
-The Reproducibility Factor: For serum proteomic profiling to be widely accepted as a diagnostic assay, scientists must show that patterns identified by mass spectrometry are reproducible across totally independent data sets. There's substantial uncertainty about whether the initial results were strong enough to support the high expectations," says an epidemiologist of the University of North Carolina. He says many of the doubts about the robustness of proteomic profiling could easily be addressed by well-designed hypothesis generation and testing.
-Peeking the Peaks. Can the pattern uncovered by mass spectrometry itself be used for diagnosis without knowing what the peaks actually represent? A bioinformatician of the University of Pittsburgh says identifying and characterizing each peak in a biomarker panel is a scientific luxury that hinders early disease detection. He adds that some diagnostic assays used today test for proteins whose identities and/or functions are not fully known, including ovarian cancer marker CA-125. "The clinician certainly doesn't need to understand the function of a blood-based biomarker that works," he says.
-Tweaking the Technology. Despite recent advances in instrumentation, proteomic biomarker discovery is still hindered by technology: current mass spectrometers are not sophisticated enough to cover the 9-to-12 log dynamic range of the human serum proteome. Scientists combat this problem on two fronts, developing methods to reduce sample complexity, and improving instrumentation. The debate is still on.
5. Suggestions to Improve Medical Scientific Methodology
5.1. Creation of an Integrative Methodological Research Strategy
Here it will be exposed the rationale of a methodological research strategy for the scientific foundation of medicine on unifying scientific principles to develop integral hypotheses.
Medical and health concepts have been called for a re-conceptualization [II,IV,74,77,85] and better interrelation of their meanings, centering them into the widest context of knowledge [14]. This must include the total exposition and application of the results of the human genome, human brain, digital human, virtual autopsy, and virtual soldier projects [29] along with others on the psychosocial phases of the life cycle of the persons, families, villages, and communities, and even on the ethnological, ethical and economic causes of the wealthy and poor populations. This must cover a parallel re-evaluation of the main results of the powerful and successful empirical bioeconomic and psychosocial scientific research [55,79,85,86].
Since the 1990ies, great international efforts have been made to increase the investments on the health research problems of the poorest populations in the countries of low and medium income, with the concepts, methods and technologies developed by the medical and health revolution of the 20-century [87,88]. However, for example, it seems impossible to overcome the microorganism resistance to the drugs against malaria, tuberculosis, pneumonia, AIDS, and dysentery, within other problems, doing only basic research on their genome sequence. In addition, much more basic research should be done on the socio-economic organization and behavior of those populations too [55]. The main scientific problems of today should be focused integrally as complex systems intertwining very different and cognitive levels [89].
The ethical values, goals and frontiers of medicine have been internationally reconsidered, as well as the main medical and health problems requiring more scientific research in all the world have been re-defined [13,14]. Nevertheless, it is necessary to select the solutions with more consensus on the philosophical anthropology problems: humanism-science dichotomy of medical sciences [II,66,78,90]; non technological-technological observation and intervention on human phenomena [16,II,66,75], mind-body dualism of man [14,II,66,75,90]. Without the adoption of solid positions respecting these universal problems, any global medical and health research strategy could be completely designed and performed.
The unified body of knowledge of medical science, in itself, should be developed without leaving out or replacing the existing medical and health sciences dominant paradigms governing today's research programs. These paradigms are among others as follows: empiricism, reductionism, static, linear, metaphysic, quantitative, algorithmic, black-box, biomedical, disease, and survival [14,66,73,75,78,90-93], which isolated from their paired paradigms distort the humane nature of these sciences. The core knowledge of medical science should be synthesized and should include the couple paradigms too as follows: rationalism, organicism, integration, holism, dynamic, reticulate or nonlinear, dialectic, heuristic, Chinese-boxes, bio-psychosocial, bioecono-psychosocial, infomedical, interpretative or hermeneutic, qualitative, suffering, health, and quality of life [14,38,55,73,75,78,90-94].
This research should be placed inside an integral framework of advanced concepts and models of the life and health of human beings within their physical, biological, cultural, economic, and social environments. All scientific theories and principles produced at every level of the clinic, laboratory, and health system, ought to be coordinated in broader theories and precepts at the clinical science inter-level, between the more reducible biological subsystems of a whole and unique individual, and its less reducible economic and psychosocial supra-systems. This would guarantee the filling in of the empty interdisciplinary and super-disciplinary spaces of the disciplinary matrix, now only full of increasing sub-disciplinary spaces.
The formalization required overtaking this unity, should be different from the first attempts of axiomatization made for classical --and even relativistic-- mechanics [36,37]. John Brown with the very rudimentary empirical knowledge obtained prior to 1770 attempted to provide medicine with the unit and structure of physics’ knowledge. Brown’s system was sustained by some physicians, scientists, and philosophers of science such as Kant and Schelling [37,43,95], but criticized as empty formalism and metaphysical speculation by many other physicians and philosophers, such as Hegel, but within the context of the non-intelligent animals. Instead, Hegel made a useful logical speculation over that limited basis --not tried again in contemporary human scientific medicine yet [95]. Now, this could be done through a broad integrative scientific research strategy, using an iterative axiomatic-like method as follows: In a first phase, the specific and inter-level theories and principles obtained from the scientific facts in the differentiated medical sciences by their necessary and successful reductionist research program could be synthesized and generalized, through a new high-level inductive reasoning. Thus, unifying principles within a general body of theory of a unified medical science might be obtained. In a second phase, original emergent hypotheses might be revealed by a novel way of deductive inference from the guiding principles, structuring and concluding them, along with the induction of accepted theories and facts, using the insuperable hypothetical-deductive method [25].
In the 19th and 20th centuries, similar thoughts have been debated, more in biology [86,86] than in psychology [89,91] and sociology [89,91]. On the one hand, an allied position have argued that biology needs inductive systematization through an axiomatic-like method to discover its own law-like generalizations and construct its self-theories [85,86,92,96]. On the other hand, an adversary skepticism have argued that in biology and in medicine, this formidable task will not be easy or helpful, because quite frequently typical biological and medical theories are best represented by families of analogically related and overlapping inter-level temporal models [97]. These representations occur very partially in human medical theories owing to the strong influence of the exclusive biomedical model, which divides the efforts to achieve their essences on an entire human level [66]. In the 1990ies, this skepticism has been weakened by the pressure of the fundamental forces of the bio-psychosocial clinical and health sciences.
The difficulty to achieve the unified medical science, greater than with an integrative biology, is not only the lack of perception of the need of an integrative reasoning to synthesize the abundant research results known of those "many things" into "one or few wider things" [28]. It is that the scientific knowledge of the individual as a whole, who is a complex biological being is also a complex economic and psychosocial being, with much more complexity than that of the simple sum of the biological, economic and psychosocial beings [89].
The central concepts, purely hypothetical states or idealizations of that medical unified science, must be studied by analogy with those of the most advanced sciences. Above all, the renovation processes needed by the relativist and quantum mechanics and physics, and by the contemporary free-market economy, regarding their classical stages of progress, must also be studied [76,92]. How did these theoretical forms emerge and re-emerge? How do they reflect reality? What concepts and methods did they use? Which have been their motions in time? Such means will help describe, explain and predict the deviations of the objects of reality from the ideal model, for example, considering a highest quantity and quality of human health.
Something like a complex central hard core of medical and health scientific theories, law-like generalizations, and high-degree hypotheses, with an integrated protective belt of peripheral auxiliary hypotheses, ought to be established, as well as methodological rules to avoid --negative heuristic-- or to pursue --positive heuristic-- research paths to the central core [98]. That core, would be the link of the principles or "axioms of meaning" or law-like generalizations obtained inductively from the lowest to the highest-theoretical levels, and in the last instance from the empirical level [99], including all the main cognitive inter-levels of the human being intertwined. Those basic premises would result from the progressive synthesis of the constellation of present and future specific principles, which would develop further in the measure that medical and health sciences continue their evolutionary progress.
The use of those similar structures of the mature sciences would allow the making of new types of creative inferences structuring new complexes of causes and meanings, by an inductive-deductive reasoning at new inter-levels of cognitive content. This would assist the hypothetical-deductive method in the scientific formulation of two kinds of hypotheses and law-like generalizations. First, hypotheses of the highest and global theoretical level, and second, of medium and lower levels of generalization, always linked with accepted theories and facts. In addition, it will bring about the demand to develop new ways and means to verify these more or less integral hypotheses.
Afterwards, this new theoretical formation process could be strengthened researching for qualitative and/or quantitative, linear and/or nonlinear required mathematical re-constructions and new constructions [85,86,100]. To date medical sciences’ contents and methods use very few of these formalized constructions. This seems to be due to the lack of comprehensive human medical and health concepts and models besides other reasons. The formulation of the own theoretical and logical structure of medical science will probably allow a greater and more efficient use of mathematics and informatics in medical research and practice, as well as of artificial intelligence [101].
The compilation of plenty information from publications, meetings, and personal communications, exchangeable by the Internet and other telecommunication systems, handled by these systemic, axiomatic and interpretative heuristic methods, combined in a new rational and global approach, are needed to perform this research task. Multinational cross-disciplinary virtual teams of experienced scientists in two or three main branches of medical sciences and other sciences; young scientists; and a program with an information network of electronic research collaboration are required [102,103]. The strong international electronic research network cooperation should be comparable in structure and power to the theory- and data based networks of biomedical research of the last sixty years, and to the evidence-based network of clinical trials.
The expected results would be the basis of a unified concept of medical and health science, which will strengthen all the scientific activities at the clinic, laboratory, and health system, through this emergentist integrative research strategy and its results. They should be condensed in a primer-introducing handbook of medical scientific principles, for medical and health students. This typical theoretical dictionary and new canon of essential concepts and methods would also be useful for doctors, scientists, and health professionals trying to begin or to go deeper and/or wider into scientific research, allowing better understanding of their meanings.
5.2. Use of a Recombinant Hypothesis Discovery Support System
In the 20th century, the unifying principles of informatics were discovered making the development of personal computers and of Internet possible. An important breakthrough on discovery support systems has been the “Arrowsmith”, created by the Americans Don Swanson and Neil Smalheiser, in principle, 20 years ago [104,105]. It helps to evoke (and assess) novel scientific hypotheses, using the structure of relationships in cross-specialty knowledge of computerized ideas and database. It firstly used directly the Medline database and, after the PubMed database through the Internet. It is conformed by a set of interactive software and database search strategies by Internet, to which anyone can gain access to perceive implicit relationships and connections that may never have been made explicit in a published form. They use the categories or subheadings of Medline, allowing the finding of the new cause, cure or preventive measure. For instance: exogenous factors as deficiency states, dietary factors, protection factors poisons, toxicity, drugs; or intrinsic factors as the genetic one. Besides the etio-pathogenic, therapeutic and preventive approaches, it could anticipate adverse drug reactions, identify mechanisms by which agents modulate cellular or organism responses, and identify potential animal models for human conditions [105].
This brilliant idea of the 19th century was re-captured in a non-automated form in 1986 [106]. It extends the power of PubMed (-1952-2006-) conventional searches, based on the premise that results developed in one area of research can be of value in another without anyone being aware of the fact. It could also be used with Biosis, Embase, or Scisearch Internet databases, and across databases conjoining all the latter ones and the new ones of Pubmed. The system works with probabilistic correlation data-driven research of new recombinant hypotheses, as an aid to the classic hypothesis-driven scientific method. Afterwards, this automated data-mining technique has been used in enormous datasets of genomics, proteomics, and imaging [107]. In the future Arrowsmith is probable that perhaps will use the whole huge databases of the E-biomed project too [108], broadening all the current PubMed titles with ad hoc and post hoc abstracts of at least 100 words, as well as extending the database from 1952 to 1800 or before; completing two centuries of partial scientific ideas and results of medical and health sciences. It could also have the possibility in the future, to work with fragments of the discussions of the papers [109]. However, it is requiring the improvement of its target search-strategies making use of unifying principles. Thus, using it, new integral solutions and even much more partial ones to classic and emergent diseases, suffering and health problems could be expected to be achieved [109].
5.3. Use of a Modeling and Simulation Research Design Optimizer
The American Richard Satava writes, “the process of a new scientific method has been alluded to by scientific savant Stephen Wolfram in his book “A New Kind of Science”. The author repeatedly refers to the power of modeling and simulation and the importance of an iterative optimization of the model. Build the computer model, add the data from real world experiment, see if the results match real world expectations, change the input data to more closely approximate the model, and run the next iteration, and so on. This is continued until there is concurrence with the evidence of real world results. Stefan Thomke also emphasized this process of iterative optimization by his hero Thomas Edison, in his book “Experimentation Matters: Unlocking the Potential of New Technologies for Innovation”…. He has focused upon the importance of not only the creativity of new technologic ideas, but also the iterative proof of the scientific method that gains the acceptance by the scientific community and public at large. The result is that world of science has (unknowingly) changed the scientific method to include an additional step between the design of the experiment (or trial) and the conduct of it. This step is Model, simulation and prediction –by repeated iteration to optimize the design of the experiment– and then proceed to conduct the experiment. This appears to be the (a new) scientific method, or perhaps it should be designated the (or a) simulation method of science. However, to what practical ends should this new idea be embraced is a matter of opinion [29].
Healthcare has no computer representation of its “product”, the patient, although the emergence of total body scanning provides the first step into this area of “computer representation of our patients”. The military has a research project, the Virtual Soldier, which is taking the first steps toward creating such a computerize patient (or soldier). This computer model, called a holographic medical electronic representation or holomer, actually exists in the computer (and on the soldier’s electronic dog tag) as an information surrogate for the soldier. The holomer is also a visual electronic health record. Once it is learned how to approach our patients from this radically new perspective (that is, viewing their holomer representation in ‘information space’ on a computer), it will be possible to catch up with the rest of the scientific community and extend beyond the traditional scientific method to the new simulation method - and rapidly expand our capabilities [29].
Today in patient care, if each person had their own holomer, it would be possible to simulate a treatment option before prescribing a medication – for example a patient with an arrhythmia could be given a virtual dose of digitalis to see if the arrhythmia would resolve, and if not, the dose could be adjusted until the holomer’s arrhythmia ceased. Or for a complicated surgical procedure, the surgeon could rehearse the simulated surgical procedure on the patient’s holomer before operating upon the patient. Any errors in drug dosage or surgical technique would occur upon the holomer, not on the actual patient. Today in clinical trials (of a new drug, device, procedure, etc) hundreds of patients are subjected to a new, unproven treatment (and compared to controls) over a short fixed time (usually 3 to 10 years). In an analogy to other disciplines like weather, aviation, manufacturing, why not create a database of de-identified models (holomers) of a million different patients and conduct a clinical trial over 50 years of time – and simulate the results in one weekend on a supercomputer, with no risk to any patient. The purpose is not to do away with clinical trials or basic scientific research, but rather to dramatically decrease the resources and time to conducting numerous experiments on the road to final experiment that provides the conclusive results. The principles of the scientific method have served us well for long period of time; however, the new technology and methodology that exists today (and is being used by others in the scientific community) can leverage off the traditional scientific method to the simulation method and elevate scientific inquiry to an even more productive plateau. If the remainder of the scientific community embraces modeling and simulation, so too should medicine, whether in daily clinical practice or in rigorous clinical research [29].
5.4. Enhancement of Clinical Scientific Hypothesis Creativity
Today many clinical physicians and investigators know well the “state of the art” of the several and diverse fields of clinical practice knowledge and technology by textbooks, journal reviews, task forces, and guidelines for clinical practice and education. They are very worried about the statistical design and informatics’ data base of their clinical research as well as of the good clinical practices in the research; all rules created by non physicians and non clinical physicians. However, not too many of them know the “state of the science” of clinics, the last original research models and articles, the evidence or lack of evidence and favorable or unfavorable results found; the flaws and challenges; and they expressly minimize the importance of the few scientific clinical hypotheses and theories existent, and are not worry about any clinical scientific law at all. They are the most common empirical clinical investigators.
Clinical physicians and investigators frequently start a research from an intuitive empirical hypothesis of very low level of theoretical abstraction, very near to the practical prevention, diagnosis, prognosis, therapeutic or rehabilitation technologies efficiency, with very few or any theoretical sustentation. They confuse the concept of clinical hypothesis with the null (H0) and alternative (H1) auxiliary statistical hypotheses, and let all these issues to the clinical biostatistician or the statistical mathematician, simplifying at the extreme the most creative part in where they could contribute in the whole design and performance of the clinical research, trial or survey. This confusion of the scientific theoretical method of the hypothesis formation and deduction of the research model to test it, with the supplementary statistical hypothesis testing is not exclusive of medical science, it happens in other sciences too [8].
The formation of scientific hypotheses and the design of statistical hypotheses are essential to modern clinical, surgical and psychiatric research. In fact, the design of statistical hypotheses depends upon the previous formation of a scientific hypothesis, which must be based on deduced facts coherent to the clinical theory and logic. It should be much more focused the scientific hypothesis formation before the step of design of statistical analysis in clinical research, in order to advance clinical creative thought scientifically more effectively.
Over the past 60 years, the application of efficient experimental, quantitative, epidemiological and computing algorithmic methods has furthered the progress of large applied empirical screening and confirmatory randomized and blind clinical therapeutic, diagnostic, and preventive trials [110]. At the same time, however, the development of the very scientifically creative initial observational, qualitative, and pre-computing heuristic methods for exploratory, descriptive, explanatory, and interventionist small clinical discovery trial and surveys have remained virtually stationary. Several factors could explain this situation:
Because clinical judgment is primarily used to discover routinely more operational scientific hypotheses about a particular state or process of an individual patient during clinical care, it has lost appreciation for its value in the discovery of more creative conceptual scientific hypotheses about particular and more general state or process in one or few more patients; hypotheses that could be useful in a broader clinical scientific sense. Although part-time and full-time clinical investigators have now better abstract scientific operational training, yet most of them lack adequate clinical scientific conceptual background in scientific method and logic of clinical medicine research, to know how much they can expect of the statistical and informatics’ techniques.
If these clinical investigators fail to do their own basic clinical research, they will lose the scientific skills necessary to perform the rigorous clinical trials and surveys suggested from outside of the clinics, most of all by the scientific hypotheses developed by the full-time experimental, industrial, and epidemiological investigators. To help discover general scientific hypotheses of inside the clinics, and pre-test them virtually before beginning the research performance, the data-driven computerized systems explained before could be used.
Although this approach is useful, some suggestions are important: 1) heuristic and discovery rules about clinical judgment have to be more studied and make more explicit; 2) training programs in clinical research process must offer a more thorough conceptual background for clinical medicine scientific method and logic, clinical medicine statistics and informatics; and 3) there must be more part- and full-time clinical investigators dedicated to the theoretical formulation and to evidence test of new scientific hypotheses factual deductions that aim at improving basic clinical knowledge --not only clinical technology-- in the clinical sciences.
Each of these measures could help the clinical judgment method regain an appreciation for being able to discover new general scientific hypotheses. To improve the efficiency of clinical research projects and programs, the clinical biostatistician, lab experimentalist, and field epidemiologist physicians, studying clinical medicine, must work together with the clinical, surgical and psychiatric researchers, to help him/her to develop scientific heuristic and creativity rules to formulate general scientific hypotheses from the starting points of view of the clinical judgment. By drawing on progress in the basic research of clinical sciences, the now implicit procedures used to discover new general scientific hypotheses will become explicit, and their future formalization and computerization will become easier and quicker.
It is also needed much more imagination, intuition, to create more rules and algorithms of clinical scientific creativity and develop heuristic and scientific methods for clinical theoretical hypothesis and even for empirical hypothesis formation. These improvements are needed in the evidence screening and confirmation design of clinical trials too. Clinical trials of new diagnostic, prognostic, therapeutic, rehabilitation, and preventive technological products, procedures, or factors should be improve clinically much more especially in its first phases.
The usual clinical trial phases are: phase I, beginning with one and continuing with few patients to explore safety early effects and doses; phase IIa, with a still small group of patients with comparison before-after in each patient for efficacy targeting and administration ways; phase IIb with two or more randomized groups, double- or triple-blind for efficacy detection versus a placebo; phase III with two or more randomized and blinded groups for more efficiency or equivalence determination versus a standard therapy; and for phase IV, with larger population using the product or procedure after the commercial use to monitor safety late and paradoxical undetected effects in the long-term [111].
All the previous work of the clinical investigator to the clinical research protocol making precise observations working with the individual patient at the bedside or consultation office in the clinics or community [112], and exchanging and studying the scientific experiences of other investigators and the state of the science, usually is not seen as a part of the scientific method in medicine and is not well estimated. It happen the same with the scientific exchange and study of the specific scientific literature of the clinical investigator together with the clinical laboratory, radiologist, pathologist, immunologist, and genetics researcher, and with the pre-clinical laboratory experimentalists in the academia and industrial laboratories. Here is where the first empirical hypotheses could arise, supported by a theoretical clinical hypothesis or suggesting a new theoretical clinical hypothesis that should be written, studied and founded scientifically. It is in this moment of the whole scientific research process that the research can produce or not scientific theoretical implications and developments at the medical and clinical basic sciences, and when the first factual deductions of the hypothesis suggest the first pre-clinical assays to design and perform in cultures of animal or human tissues, cells, chromosomes, or genes, and/or in the pre-clinical physiological or pathological animal trials.
The clinical empirical research of new technologies or procedures with its theoretical derivations can acquire the peak complexity when began the first two clinical trial phases, which have been described as more basic or pharmacological. It is then when the experimental and clinical research can continue producing theoretical implications for the enrichment of the hypotheses and theories of the basic clinical medicine, surgery or psychiatry, and other medical sciences. The rest of the huge and detailed clinical statistical methodological systems for clinical research phases IIb, III and IV of randomized and blinded trials with all the good clinical practices are more routine, necessary but no sufficient for clinical and medical discovery, invention and innovation, which arise before them.
The same can be said for the clinical non-interventionist research, which are not all surveys. The key for the discovery of new physiological and etio-pathological knowledge is the observational investigation of case studies and small number of patients, correspondent to phases I and IIa of the clinical trials, and after the pre-clinical research together with non-clinical scientists of the academy. Afterwards, can become the case-control and exposed-control investigations, to confirm successively the intensity of the causal association of factors with the appropriate statistical odds ratios or relative risks coefficients and significance tests.
Another main problem that has today the clinical medicine establishment is that the medical scientists have to be much better prepared in medical research. First, in the methodology and logic of the in depth research of the medical systems in all the factors and relations related to the scientific medical and health problems; and afterwards, in medical statistics, informatics, and other sciences. In the last decades, the control of confounding variables and prognostic factors have been done, using analysis of covariance, and multivariate regression techniques stratifying in the analysis of the results –even comparing with historical controls [113,114]. It is also frequently used the stratification of patients by known prognostic factors --before the randomization and treatment-- in the design of the trials and studies, letting at random the rest of unknown variables. There has also been used clinical data bank long-term research [114]. These are important aids, but in a certain way have distracted the clinical physician of their first responsibility in their clinical investigations. This is to do their first medical job, studying intensively their medical systems discovering most variables and relations without statistics.
How can be elaborated that specific methodology of medical science for more hypothesis-driven based research that should be used before consult the medical statistician, and to do all the data-driven based research, it is a core need of current medical and clinical science and research of this century, but out of the objectives of this essay.
5.5. Underlying Theoretical and Philosophical Problems of Medical Science
Now, it is the turn to the most intuitive discussion of a rather delicate matter concerning a notoriously difficult subject, “the incomplete application and adjustment of the scientific method to the clinical medicine reality of the individual patient and group of patients, and the incomplete foundation of the clinical medicine science”, and how this could be solved by the next generations of physicians, some of them doing theoretical clinical investigation besides the empirical clinical investigators, as physics, chemistry, and other sciences have done.
First, it will be discussed the very interesting statement of the Greek medical oncologist Dennis Razis in his paper “How progress has been achieved in medicine”, which is as follows: “In theory and methodology the change has been from determinism to indeterminism in all sciences from microscopic physics to biology. Now, statistical association is almost never one hundred or zero percent“ [11].
However, that determinism of physics, have very scarcely arrived yet to even macroscopic medicine, with our without mathematical functions. Few medical laws have been structured in a determinist form in physiology only, although they must exist in all medical phenomena too. Medicine has passed directly from the pre-scientific statements with none or poor evidences through the statistical techniques to most scientific statements with much more evidences and usual probability values of confidence between 0.001 and 0.05. The embryo of determinism that could have been developed more in medicine between the 18th and 20th centuries was miscarried by Pierre Laplace’s powerful suggestion of indeterminism to medical therapeutics decisions. To analyze in depth this idea, firstly it should be examined some crucial thoughts of Laplace, Karl Pearson, and Albert Einstein, on this matter in science.
Pierre Laplace in his ”Philosophical Essay on Probabilities” had stated about determinism, for an obvious reason. For him, probabilities lead to rational inferences in situations of incomplete knowledge. He explicitly cited medical therapy as a possible domain for applying the calculus of probability. He said, “It must be distinguished different levels of analysis. Our knowledge is incomplete, and we have to live with that. That is why probabilistic reasoning is extraordinarily successful in practice, but when it works; this is due to our partial knowledge” [7].
This is true and probability has helped very much and must continue helping clinical medicine as science of particulars and of generals, in decision-making in partial knowledge conditions. However, decisions on therapeutics were not in the 18th century, and are not even today the only and main object matters of scientific research in clinical medicine science of general. Moreover, the completion of scientific knowledge in all the medical systems, included the therapeutics, it should be precisely, the major labor of science in clinical medicine.
Karl Pearson lacked Francis Galton’s originality… but it was his zeal… that created the statistical methodology and sold it to the world. Galton had a thought: “In science credit goes to the man who convinces the world, not the man to whom the idea first occurs” [115]. This happened with Galton’s correlation coefficient, which has passed to history as of Pearson. However, Pearson, a mathematician who did not study the medicine career, wrote in the “Grammar of Science” a crucial thought to understand one of the medicine maximum hurdles yet. He said, “The very statement of the law of causation involves antecedents –sameness of causes-- which are purely conceptual and never actual. Permanence and absence of individuality in the bricks of the physical universe are only demonstrated in the same way than the bricks of a building are for many statistical purposes without individuality. The exact repetition of any antecedents is never possible, and all we can do is to classify things into like within a certain degree of observation, and record whether we note as following from them are like within another degree of observation. Whenever we do this in physics, in zoology, in botany, in sociology, in medicine, or in any other branch of science, we really form a contingency table, and the causation of the physicist solely results from the fact --not that the contingency coefficient of everything physical is unity-- but that he has so far worked to most profit in the field, where his contingency is so near unity that he could conceptualize his relationships as mathematical functions” [7].
At this step of the examination of the evolution of the modern scientific method and foundation in clinical medicine, it would be interesting to exam the theoretical homologies that could exist with the quantum mechanics theoretical, methodological and philosophical problems in the 20th century. This will be done to see if there could be extracted some valid and useful experiences and suggestions that could help the clinical investigators, to use all the potentiality of the scientific method and give a more comprehensive scientific foundation to clinical medicine, surgery, psychiatry, all increasingly depending from the outside statistical and techniques and epidemiological approaches since the past century. It will be used a summary of three discussions of the Paul Gross, Norman Lewitt and Martin Lewis’ book: “The Flight from Science and Reason”, and the three chapters of The Foundations of Physics: “Quantum Philosophy” by Sheldon Goldstein of Rutgers; “Physics and Common Nonsense” by Daniel Kleppner of MIT; and “Science of Chaos or Chaos in Science” by the Belgian Jean Bricmont [6].
The theoretical and philosophical problems arisen after the foundation of statistical mechanics in the 19th century and of quantum mechanics in the 20th century, based on the “randomness” and “indeterminism” to reality, conducted to the creation of a “quantum philosophy”, and to a long discussion among the greatest physicists and mathematicians [6,V].
A very brief summary of statements of the “quantum philosophy”, based in Werner Heisenberg and Niels Bohr’s thoughts is as follows:
-“The idea of an objective world whose smallest parts exist objectively in the same sense as stones and trees exist, independently of whether or not we observe them… is impossible”.
-In few words, the wave-particle duality has the problem that although it can be measured the
wave diffraction and photoelectric effects separately, they cannot be measured with accuracy both properties at the same time. According to the complementarity’s principle, physical entities can display properties that are fundamentally incompatible.
-“In the microscopic quantum domain the laws of nature involve irreducible randomness”.
This “Copenhagen Interpretation” was accepted almost universally by the world theoretical physics community, excepting Albert Einstein and Erwin Schrödinger [6,V]
The clear constructive response of Einstein was as follows: “I am, in fact, firmly convinced that the statistical character of contemporary quantum theory is solely to be ascribed to the fact that this (theory) operates with an incomplete description of physical systems…. [In] a complete physical description, the statistical quantum theory would… take an approximately analogous position to the statistical mechanics within the framework of classical mechanics”. Part of what Einstein was saying here was that (much of) the apparent peculiarity of quantum theory, and in particular its randomness, arise from mistaking an incomplete description for a complete one [V,6].
Afterwards, John von Neumann, one of the greatest mathematicians of the 20th century said: “Einstein’s dream, of a deterministic completion or reinterpretation of quantum theory, is mathematically impossible”, and von Neumann claim was almost universally accepted, and followed by most of the world scientists. However, in 1952 David Bohm, through a refinement of de Broglie’s “pilot wave model” of 1927, found just a reformulation of quantum theory. Bohmian mechanics was precise, objective, and deterministic—not at all congenial with quantum philosophy and a counterexample to the claims of von Neumann. Nonetheless, the “Bohmian theory” and the “hidden variables theory” continued both in doubt for more that a quarter of century [6].
There was another opponent of Einstein claims, John S. Bell who had interesting reactions and re-analyses of that phenomenon. He said, “In 1952 I saw the impossible done. It was there in the papers of David Bohm. Bohm showed explicitly how parameters could indeed be introduced, into nonrelativistic wave mechanics, with the help of which the indeterministic description could be transformed in a deterministic one. More importantly, in my opinion, the subjectivity of the orthodox version, the necessary reference to the “observer”, could be eliminated”. Bell asked himself, “But why then had Max Born not told me of this "pilot wave"? If only to point out what was wrong with it? Why von Neumann did not considered it? More extraordinarily, why did people go on producing ‘‘impossibility’’ proofs, after 1952, and as recently as 1978? ... Why is the pilot wave picture ignored in textbooks? Should it not be taught, not as the only way, but as an antidote of the prevailing complacency? To show us that vagueness, subjectivity, and indeterminism, are not forced on us by experimental facts, but by deliberate theoretical choice?” Bell continued: “It is not clear from the smallness of the scintillation on the screen that we have to do with a particle? And it is not clear, from the diffraction and interference patterns, that the motion of the particle is directed by a wave? De Broglie showed in detail how the motion of a particle, passing through just one of two holes in screen, could be influenced by waves propagating through both holes. And so influenced that the particle does not go where the waves cancel out, but is attracted to where they cooperate. This idea seems to me so natural and simple, to resolve the wave-particle dilemma in such a clear and ordinary way, that it is a great mystery to me that it was so generally ignored” [6,V].
Based on the recent experience with the quantum theory, could be deduced that medical theory has been operating with an incomplete description of medical systems. The deterministic completion or reinterpretation of medical theory could be made with and without mathematics by the moment. With the already discovered medical theory and facts in the last 200 years, some clinical medicine theory could be reformulated in a more precise, broader and deterministic central corpus of theory, where present diagnosis and therapy of diseases scientific matters, continue being one applied branch with most practical and direct consequences. The core creative clinical research in all it forms, as well as in the basic sciences, and epidemiological-health sciences, should be the discovery of the hidden factors and hierarchization of the variables and their relations of the clinical, pre-clinical, and post-clinical systems. In the medical systems under study, when most key variables be discovered, the contingency coefficients could be so near unity, that will become unnecessary the probabilistic statement, the randomness could be very reduced and the systems can be explained scientifically with deterministic statements and mathematical functions as is usual in physics and other hard sciences. The discovery of the hidden variables must be done by the clinical investigator with keen interest in the clinical exploration of the whole patient and the whole natural and social environments where the patient lives, from unusual degrees of observation and levels of analysis, as have done successfully physicists, chemists, molecular biologists, and even economists, in their specific systems. It must be taken into account all direct objective and subjective evidences as well as all the interventions experienced by and done on the patient and his/her detailed responses, as well as all indirect evidences by all the instruments of diagnosis and of biologic, economic, and psychosocial evaluation.
Second, in the absence of enough empirical evidences on the human sciences and of a scientific clinical judgment method for medicine, the Queteletian and Laplacian scientific approaches to the physiological constants and clinical judgment with probabilistic mathematical precision has produced very important advances in medicine until the 21st century. Medicine could diminish the use of obsolete home remedies and quackery. However, medicine advanced much more in etio-pathogenesis and preventive knowledge, in diagnostic and therapeutic technologies of disease, than in the knowledge of the physiological complete human being system and the methods to maintain it healthy entirely in body and mind at the same time.
Therefore, the task of the full application and adjustment of the scientific method and foundation of medicine stays unconcluded. The scientific hypothesis-driven method and logic of medical facts and system was completely substituted for the logic of statistical inference in randomized clinical trials and surveys and even recently in data-driven discovery and modeling-simulation systems. The body-mind duality approach has guided medicine for 350 years, maintaining an increasing dissatisfaction in the patient that is much more than a animated body, and therefore, maintaining an opposition of the western scientific medicine with the Hindu Ayurvedic and Chinese Taoist, among other eastern pre-scientific schools of medicine, which relatively are much more centered in the mind than in the body, and in the use of the mind to heal the body. Nonetheless, it is probable that the integration of the best of the oriental medicine have to wait for more empirical evidence and theoretical explanation that finally describe and explain the complete scientific picture of the body-mind unity. In the meanwhile, it seems necessary to pass through rigorous clinical trials with necessary methodological adjustments, the more logical and serious natural and traditional medicines and techniques in each country, publishing always their confirming or disconfirming results.
Third, one rational basis of the scientific rejection in the West of the oriental medicine practice due to scarce and weak scientific theory, as well as other similar theories dealing with the mind and social matters, could be found in Karl Popper’s “Logic of Scientific Discovery” and other books, which guided successfully natural sciences for the last half of the 20th century.
Popper had to escape from Nazism in Vienna to New Zealand. He lived the rise of the Marxist social theory after the emergence of Lenin and Stalin’s Communism, and the Hitler’s National Socialism-Nazism, Mussolini’s Fascism, and Franco’s Falangism [VI]. These left and right wings of modern totalitarianism, restored captive societies and economies for about 74 years in the 20th century. If the formulation of Popper’s falsification system for science, excluded psychosocial sciences to defend the human kind from those social and similar theories (included Freud’s psychoanalytic theory) or not, it could be better known someday.
He said, “These psychosocial theories were non precise theories, which were not open to critical thinking and could not be falsified as the physical and other natural ones, because in Popper’s terms they were perfect since its emergence. In Popper’s last decades his pessimist anti-induction logic system with its falsification tool fell in discredit when he created the verisimilitude tool to balance his logic of science with an optimistic approach on the scientific truth, due to logical contradictions in its construction” [VI]. In 1989, thanks to the end of a seven decades social experiment, it was demonstrated that Marxist economical and social theory was not perfect but rather a pseudo-scientific dogma, and worldwide publicly falsified by enough evidence. Even so, new generations of logics of science must develop more complete logic discovery systems including non-falsifiable economic and psychosocial theories.
Popper has published on the mind-brain problem, formulating and discussing a new aspect of the theory of mind. This theory was partly based on his earlier developed interactionistic theory. It took as its point of departure the observation that mind and physical forces have several properties in common, at least the following six: both are: (i) located, (ii) unextended, (iii) incorporeal, (iv) capable of acting on bodies, (v) dependent upon body, (vi) capable of being influenced by bodies. Other properties such as intensity and extension in time may be added. He argued that a fuller understanding of the nature of forces is essential for the analysis of the mind-brain problem, and stressed the relative autonomy and indeterministic nature of mind [39]. Lindahl and Arhem, Popper’s collaborators, after his death commented his theory of the mind as a force field. “The survival and development of consciousness in biological evolution call for an explanation. An interactionistic mind-brain theory seems to have the greatest explanatory value in this context. In Popper’s theory, the distinction between the conscious mind and the brain is seen as a division into what is subjective and what is objective, and not as an ontological distinction between something immaterial and something material. The interactionistic hypothesis is based on similarities between minds and physical forces. The conscious mind is understood to interact with randomly spontaneous spatio-temporal patterns of action potentials through an electromagnetic field” [116].
Gesmund Hesslow has defended a pragmatic version of mind-brain reductionism from a neuroscientist's point of view. Opposition to reductionism comes from both philosophical and empirical quarters. He argued that philosophical arguments, such as semantic problems with the concept of identity, are unconvincing and should be regarded with the greatest suspicion. The most influential empirical result that has been claimed to constitute a problem for reductionism is the temporal delay and mental antedating of consciousness found by Benjamin Libet. Hesslow argued that these results, far from being a problem for reductionism, constitute evidence for a particular view of the physiological origins of consciousness. Finally, he argued that many subjective aspects of experience can already be given satisfactory scientific explanations and that scientific progress is likely to rob the mind and subjective experience of their mystery [117].
Nonetheless, the body-mind unity problem is not solved yet and its solution is also a need of the external logic of clinical medicine to satisfy the public health demands, focusing much more the quality of the biological, economic, mental and social health with the life lengthening.
Finally, it will be made some comments on the scientific theoretical tasks and methods that should used the present and new generations of physicians to solve these philosophical problems of clinical medical science. Clinical medicine surely could have some isomorphic systems with the systems in physics, and the clinicians, surgeons and psychiatrists could have similar possibilities to have new “dreams” at the style of Albert Einstein about medical theory and human physiological systems, and to explain more than ever the human physiological phenomena and dilemmas, as for instance the body-mind dilemma, in a “similar way” as David Bohm explained the wave-particle dilemma with a deterministic approach to reality, after Einstein corrected the interpretation of the theoretical and methodological void.
Diverse creative scenarios are open to the theoretical clinical physician investigators taking this example as a starting point of view. Clinicians could retake again in the 21st century the Claude Bernard determinism claims in the 19th century or not, taking advantage of an enormous richer status of scientific medicine in empirical evidences, knowledge, and maturity.
Physicians will have to discover new ways to solve the body-mind duality stated by Descartes in the 17th century, centering also their attention in the mind, and not letting relatively it aside, to be able to describe better the human health system finding with much more work in the human physiological system the hidden variables, which their transitory absence have made seem to most physicians and mathematicians between the 18th and 21st centuries, that all human health phenomena in medicine had an “irreducible randomness”, which can only be handled indirectly by the statistical inference, and not directly by the clinical inference and even by mathematical equations too as the hard sciences do.
All the informatics data-driven discovery support systems, could help to find those hidden variables of the human physiological system, as well as the modeling-simulator system, could help to optimize the clinical research design, conduction, and results, better, if most hidden variables have been already discovered. However, nothing seems that could substitute by the moment the basic hypothesis-driven method of clinical judgment, if is use by a well trained clinical investigator to discover the hidden variables of the diverse human being whole system and its subsystems in his/her patients at the center ward, office, and home with the family.
The scenario is open also for the clinical investigators who can wake up and convert them in the first defenders of the more advanced science of clinical medicine with probabilistic and determinist statements at the same time, as made John S. Bell, to discuss for many decades these matters with other clinical investigators still impressed by the statistical mathematicians and the status quo defenders by the law of minimal effort, to be able to put scientific method in clinical medicine science and its scientific foundation in a more advanced scientific status for the benefit of the individual patient.
Finally, the scenario is opened also for the mathematical investigators to develop together with the theoretical clinical investigators newer human and clinical mathematical models and techniques to characterize, describe, simulate, explain, experiment, and predict the complex human being systems behavior by computer simulation and other means. The discovery of deterministic mathematical functions and equations has been long dreamed by physicians and mathematicians since centuries ago to raise medicine to the status of a mature science.
6. Isolated Medical Scientific Research Methods and Strategies
6.1. Clinical Ortho-Investigation Crisis before Meta-Investigation
As the medical scientific health care, medical scientific research is passing through a worldwide progressive crisis, especially in the last three decades. Its effectiveness has been diminished to achieve the humanistic goals of medicine. The impact of its outcomes on the health of persons, families, and societies has remained stationary. The medical research costs along with the expenditures of health care have been multiplied [13,14]. The clinical medicine ortho-investigation of high quality, guided by internal scientific forces, originated-in-the-patient and investigator-driven, has passed to a second plane for the physician generalist as well as for the specialist [15].
Since the 1950ies, the development by biological procedures of basic knowledge about medical models, along with the advancement of new means for medical care through the technological development of bio-pharmaceuticals and bio-equipment/devices, and bio-procedures (and recently of natural products) most of them in the research industrial laboratories, has become the first leading external force of medical progress logic. In addition, the improvement of better public health's indexes of deaths, disabilities, diseases and risks has been a second prominent although less powerful external force of progress [12-15]. The clinical medicine meta-investigation for the evaluation of the technological outcomes of the research laboratory, guided frequently by the present health indexes, is considered the most rigorous clinical medicine research, because it is an extension of the laboratory research in correspondence with public health. Nevertheless, without clinical ortho-investigation the necessary skills to continue doing good clinical meta-investigation are lost [27], and more important, the solutions of the more psychosocial and even economic lifestyle and health problems of the person and his family and community as whole objects of research are delayed, because the technology-oriented and index-driven researches are up-today blind for them.
A study between 1953 and 1965 of 7,000 medical research abstracts, presented annually in a US national medical meeting, indicated by their aims, materials and methods, a new trend in its direction: Less research toward clinical medicine patient-centered from 40% to 16% and more toward nonhuman/non-disease or basic phenomena from 6% to 26% [16]. A study of 612 articles in three journals (NEJM, Lancet, and JAMA) from 1946 to 1976 revealed an increase of weak research designs (maintaining one third with ten subjects or less) and of clinical trials from 13% to 21% --randomized from 0% to 5% [17]. Lastly, other 444 articles between 1971 and 1991 of those same journals, exhibited an increase in clinical trials from 17% to 35% --randomized from 31% to 76%--, multi-center studies from 10% to 39%, and health service research from 0% to 12% [18]. The proportion of investigators applying for clinical research grants from the National Institutes of Health (NIH) who are physicians has declined from 40% thirty years ago to 25% today [118,119].
In the last two centuries, medical research has been progressively diverging mainly in two fields: clinical medicine research --including clinical epidemiological research-- and non-clinical medicine or basic medical research [20]. Recently, epidemiological and other public health investigations, a broadest third field [120,121] not so widely accepted, is attempting to include medical research. For instance, in 1995, The John Curtin School of Medical Research, international center of excellence within the Institute of Advanced Studies of Australia, said that "it is focused on basic aspects of biomedical science," and "it must be able to demonstrate the clinical medicine relevance of its fundamental innovations," coordinating with different clinical study units nationally and abroad [122]. Only for the latter, they planed to construct a Center for Clinical Studies. Therefore, the dominant training of medical researchers is to date on basic research in laboratories.
The scope of clinical medicine research methodology has become centered gradually on better-designed and analyzed randomized trials, and on retrospective meta-analysis of their results. In the 1990, its interest has become aimed at doing prospective meta-analysis of groups of major multiple centers and countries' clinical trials with dozens of thousands of patients [123]. In the mid-1990s, China has become the greatest clinical laboratory country of the world due to its immense population and patients. The latter research style is to achieve enough test power to prove faster statistical significant differences in responses to new drugs and other products derived from the research laboratories of the industry. Meanwhile, the laboratories have generated methods for accelerating drug discovery, as parallel-compound synthesis [124], and many others, passing in the last decades from the most empirical and random screening, for example, made by Ehrlich in the early past century to discover the salvarsan against the syphilis, to a more theoretical and hypothesis-driven search of new products. Nevertheless, the great delay comes after the quick pre-clinical phases in laboratory models in human and animal tissues, cells, and organelles and in animal models, in the final and progressive in complexity longer clinical trials phases I, II, III, and IV, which in some cases are around 10 years searching for safety and efficacy in relation to non treated or placebo groups, and efficiency in regards to known standard products and procedures. The Cochrane Collaboration for systematic reviews of clinical trials’ themes to help setting up findings of medical research on practice has also begun since the 1990s [125,126].
In the last 60 years, basic biomedical research has prospered so much at laboratories, while clinical medicine research per se at the bedside in the ward and home, in the consulting, surgical rooms and dentistry chairs has declined, that basic research branches have been seen as the theoretical and even as the whole medical scientific research system [25,26]. Progressively, clinical research has been reduced almost exclusively to carrying out assays of new high-technology microscopic, biochemical, radiological, imaging, genetic, immunologic, and biophysical bio-pharmaceutical and reagent, bio-equipment, devices, and procedures. Even good clinical practice standards are being co-promoted if not all promoted by non-clinician and non-physician laboratory investigators [127]. Their outcomes and methodologies have converged closely, but only in an input-output unilateral way [128]. Recently, clinical medicine research methodology has been absorbed by clinical epidemiology (not causal epidemiology), which has assumed along with clinical biostatistics –with more mathematics and informatics than clinical medicine science-- the design and analysis of the clinical diagnostic and therapeutic trials everywhere, not only in the population and community, but in the academic clinic too [45,121,129]. This has left most clinicians, surgeons, and psychiatrists, practically with the old style and very questioned by the non-physicians clinical judgment method and hermeneutic-interpretative methods, in a practical interface field between real clinical research and clinical quality of care improvement [54].
This decline in the outcomes of clinical medicine ortho-research (investigator-driven) and increased growth in meta-research (non investigator-driven), occurred in the last decades of the 20th century in USA, UK and Australia, while France, Germany and Japan, maintained them, possibly due to greater national research efforts [27]. For instance, clinicians in the 1990ies were more than the 90% of the total US mainstream of physicians registered. Of that same total, only 4% (30,000) were clinical investigators [130], although not all of them scientists, more than 86% of the clinicians did not report any clinical study. The high, medium and low-income developing countries of the South have even a worst situation [13].
6.2. Clinical Science Logical and Philosophical Hurdles
Multiple causes have been involved to explain this, specially the following two: 1) Clinical practice and research have intrinsically different philosophical foundations [131], 2) Absence of active recruitment of physicians for research training at an early age [27,132]. From this, it could be derived that if a part of young creative medical physicians graduates that now are going to laboratory research training, could understand clearly that clinical and whole medical science progress really need urgently the rapprochement of both research and practice, many of them would attempt to do clinical research or both successfully.
World laboratory researchers with a medicine doctor degree (M.D.) generally do not receive a medical research methodology manual for their training. They train one to two or more years mainly in practically general mathematics [133] and other exact sciences, basic sciences, molecular biology, statistics, informatics, basic philosophy, and so on, with all their manuals, to obtain masters in science (M.Sc.) and/or philosophical doctors (Ph.D.) academic degrees, usually with basic but also with applied theses too. Tutor or mentor researchers and concrete research articles are their guide. The heart of their research methodology is the laboratory experimental research method assisted in a large proportion of their designs and analyses by biometric techniques [123].
Sanitary researchers with M.D. degrees, also make theses for M.PH. and/or Ph.D. academic degrees. They also get some guidance from tutors and research articles, but they have social and epidemiological transverse section or cohort research methods manuals based on more social- and biostatistics. They are trained one to two or more years, mainly in mathematics, psychosocial sciences, ecology, management, epidemiology, statistics, informatics, basic philosophy, and so forth, with all their manuals too. They usually make little basic and much applied research [122].
Clinical medicine investigators with M.D., usually do not study any clinical research methodology manual, except generalists in UK [134], and clinical trialists in USA, Europe, and Japan (of its elements [135] and research ethics [50]). They have a powerless training to make M.Sc. and/or Ph.D. degree theses since the undergraduate or postgraduate [27]. They are guided neither by tutor researchers nor by research articles. They receive knowledge and skills of their specialties with or without some clinical epidemiology and biostatistics, making neither research without the domain of the whole medical nor clinical research methodologies, which unfortunately are still only identified only with clinical epidemiology, biostatistics and informatics.
Teaching so many mechanical empirical methods, tactics and procedures in detail to handle the facts and data, is forgotten to teach also the indispensable critical scientific attitude, thought, strategy, objectives, programs, and the non-less important theoretical creative methods and tactics to develop the new ideas and hypotheses.
The most general methodological problem that has been dragged by medical sciences is that most investigators in clinics, laboratory and health system have never seen clearly which are the central objectives and methods of modern scientific research. They still have not grasped well the concept well expressed by the American Chemist Linus Pauling that ideas come first and (observational and) experimental studies come later; that innovative ideas (scientific conjectures and hypotheses) are the sine equa non of progress in science [136], not useless philosophy. Yet they are not aware that the understanding of scientific facts with data derived quantitatively from them is only possible through the directing and ordering role of hypotheses of low, medium and high theoretical levels [26]. The hypothesis is originated generally through the use, first, of clinical judgment, hermeneutic-interpretative and other qualitative methods of research in one subject or small group of less than the so underrated number of “ten” subjects. Thus, to begin understanding a reality in the specific context of a concrete study the latter methods acquire utmost importance [23,24]. The dominant positivist paradigm must be complemented with the interactionist and constructivist paradigms as physics with chaos theory have been doing recently [24]. Progressively, the dichotomized scientific research paradigms are becoming less divided and a unit [25].
There is a gap between the traditional role and models of classic disinterested, value-free --basic research, knowledge-driven, and the hired hand, consultancy--commissioned research, client-driven. Since the 18-century when the idea to provide medicine with the unit of physics surged [36], scientific medicine has hauled the methodological need to enrich those models of scientific research. This could be seen as to develop a model of new principle-directed, virtually fact-free --inductive research, synthesis-driven, which allows in the future the use of new hypotheses derived, value-laden beginning-- deductive research, analysis-driven model, by analogy with the more mature natural and social sciences. Therefore, over the basic and applied research developed by the hypothetico-deductive method, could be formulated subsequently by an axiomatic-like method, derived hypotheses to be proven factually [25]. However, with the development of such models, skepticism about their necessity, usefulness, and theoretical and practical difficulties, has always existed [96,97].
Nevertheless, this would be possible only if horizontal or most general research about the non-proportioned more used factual-inductive, hypothetical-deductive and quantitative methods were performed too in order to establish a balance with the scarcely utilized inductive-axiomatic, axiomatic-deductive, hermeneutic-interpretative and qualitative methods, still not integrated, in a whole domain of medical methodological knowledge [25]. To achieve the unification of vertical or more specific research methodologies, it is also necessary to stress on the methods used less explicitly in mature sciences, for instance, in modern physics and modern economics. This would allow the generation of new scientific hypotheses conceptually, from high-theoretical level down to low-theoretical or empirical level. All this development would be much before the operational step with the auxiliary statistical hypothesis testing tools arrives, and within a unique methodological system, to increase the medical, sanitary, social, and economical effectiveness and impact of research.
At present, clinical medicine research has been remained as an interface sort of research, with lack of man wholeness and healthfulness content, of secondhand knowledge extension and technology translation to clinical practice in hospitals and communities, generated in the research laboratories [129], about two centuries ago derived from clinical practice. Clinical research has practically lost the direction of medical research as a whole and even clinical research per se that it had until early in the 20th-century. To this crisis in its internal logic of progress has contributed far beyond external factors, the stress in the thought that medicine can be only a non-classical science of particulars [137]. This has aborted the enormous heuristic potential of the clinical researcher and even of the studious practitioner to generate new medical scientific hypotheses not only in practical diagnosis and therapy, but in etio-pathogenesis, prevention, rehabilitation of disease, and in etio-healthgenesis, promotion and restoration of health too. Clinical medicine judgment scientific method has solely stayed and been perceived as a simple practical application of the hypothetical-deductive scientific method with the aid of probabilities on the patient care matters [20,22,137,138]. It is still mistakenly seen without any possibility to formulate at least as primitively as before law-like generalizations to medicine as also a science of generals, which could even become hard science in the future too. To solve all these situations, along with the ideas of the individualized care of each patient [127], new integrative ideas about the achievement of general knowledge could be develop too.
7. Unified Methodological System for Investigation in Medicine
7.1. A Trans-Methodological Model of Clinical, Basic and Health Sciences
To understand how to develop a unified methodological system of medical scientific research, the first thing is to place this matter in its historic and logic context in a brief way. Medical sciences were born as a result of the use for a long time on the patients of the clinical medicine judgment method, which from its very beginnings has been a more qualitative than quantitative method [7,20,30]. Then, the later differentiation of that first general medical science in clinical, laboratory and health sciences began with their respective scientific investigations and methods [7,20,25,128]. To date medical sciences have been developed as more theoretical or as more practical sciences with the important assistance of many mature sciences like physics, chemistry, biology and even the so called “immature” sciences as psychology and sociology. The union of physicians with physicists, chemists, biologists, psychologists, sociologists, mathematicians, economists, and so forth, has made crucial contributions to medical science progress in the opportune moments [16].
This help has given scientific methods to medical sciences to create, for medical facts, the theory they needed with a measure of certainty, aiding through medical education to achieve the goals of medical and health care: less suffering, solace, illness, and handicap, and more health [14,32,139] and well-being. However, the first medical science was divided in dozens of clinical and derived laboratory and public health sciences [25]. Most of the medical sciences of today study and measure the body and its diseases through its parts, as clinical cardiology and cardiovascular surgery, clinical neurology and neurosurgery, and son forth, and the etio-pathogenesis mechanisms, as microbiology and virologist, molecular biochemistry, genetics and immunology, and so on. Only psychiatry, studies exclusively the mind and its illnesses with big difficulties to measure the functional ones yet, but not so much as its health and well-being [139]. The bio-epidemiology and social epidemiology study the whole communities and populations of bodies' illness and health, with their mutual biological and social environmental interactions. Exclusively general and family medicine are trying to study the patient and his family and community as entire body-mind units each one with their specific distresses, ill health and disabilities, and also their health and well-being, in their own environment [128].
So far, their major solutions to the scientific problems of the different parts of the human being, have contributed with many pieces of medical scientific theories and methods by each science isolated or associated, but have not well achieved the goals of medicine [14,30,139]. Paradoxically, they have increased the conceptual and methodological problems, because as not well-integrated contributions, they have not been suitable enough to deal comprehensibly with the complex medical facts of human being, as a whole unit or as a whole of units of investigation [25,128]. Medical methodology of scientific research due to all these reasons still has not its own body of knowledge, because it has not gone beyond the accurate and successful applications of the general scientific hypothetico-deductive and statistical-computing methods to the factual and vertical research in the clinic, laboratory, and health system. This less than eclectic status is limiting the enormous potentials of progress that medicine has today [25].
This situation disintegrates the harmony of the unique creation process of medical research. This process is complete, dynamic, continuous, basic and applied. It begins in the creative medical practice in any research field and moment –physical or virtual clinic, laboratory, and health system--, and finishes generally in the common clinical medicine and public health practices, only to start again, improving theory and practice iteratively. Medical investigations in those specific subsystems have to be conceived also as essentially related fields and moments of only one creative process to solve medical scientific problems, which must integrate multilaterally their methodologies to achieve more efficacy than when they are only used separately.
The results of the researches among those main fields could coincide in more or fewer distant moments, as can be understood examining just some examples. In 1747 an English surgeon's mate, James Lind, of the Royal Navy in Salisbury, carried out what may well have been the world's first clinical trial. He demonstrated clinically with simple research that oranges and lemon juice cured scurvy, but he could not explain why. This discovery had to wait to 1795 to be accepted and then the disease began to be prevented, more than a century before vitamin C was isolated as ascorbic acid, and its biochemical role elucidated by complex research [0,17]. In 1881, a Cuban general practitioner-ophthalmologist, Carlos J. Finlay in Havana, suggested by clinical, laboratory, and epidemiological investigations that yellow fever was transmitted by the female Culex mosquito [121]. No one believed in his discovery until was confirmed by other studies performed together with an American clinician in 1901. However, his hypothesis became accepted and practiced successfully in prevention campaigns since then, before the isolation in 1921 of the specific yellow fever virus, the creation in 1937 of specific anti-viral vaccines, and despite the lack even today of effective antiviral drugs against the virus different strains. In 1920 a Canadian children’s surgeon Frederick Banting and a medical student Charles Best in Toronto, helped by a physiologist and a biochemist made another major discovery isolating insulin from dogs' models for diabetes mellitus insulin-dependent control. The thing is that now 85 years later, the omens of its control and of the insulin-resistant type of diabetes derived later are not so good yet. Their incidence and prevalence have increased, presumably due to the action of environmental factors, which still have not been completely discovered to prevent both, the diseases and its complications [16]. In 1929, an English laboratory researcher, Alexander Fleming, described the antibacterial properties of an extract of the common mold penicillium notatun. Penicillin was given to a patient for the first time in 1941, in Oxford, after studies carried out by a pathologist and a chemist on mice models, sponsored by a modest grant of the US Rockefeller Foundation, because in UK anyone wanted to give him a grant to do it [16].
Medical scientific research requires at least four conditions to be integrated methodologically in its broadest sense: First, the integration of its own philosophic, anthropologic, ethic, ontological, epistemological, logic, historic and axiological fundamentals, which are also general foundation of the dominion of the scientific methods of clinic, laboratory, and health system scientific investigations. Second, the synthesis of the specific norms and skills of good common medical practice --without forgetting that also is a best practice a good theory. This includes the set of auxiliary and specific scientific tools, technological and non-technological, specially, the physician-patient, physician-family, and physician-community relations, as “medicine” for themselves, among the preventive, diagnosis, prognosis, preventive, therapeutic and rehabilitative means too. Third, the assimilation of models and methods of health and economic organization and management, and the generation of the suitable climate to encourage creativity and actively support good ideas [140], hypotheses, protocols, research data, scientific outcomes, and their reports, besides the quick application of the results in the current medical practice with a cost-effectiveness criteria. Fourth, the development of clinical judgment, besides new methods for the etiologic, diagnosis, therapeutic, rehabilitative and preventive human modeling, experimentation and prediction by computer simulation [29], formulation of scientific medical hypotheses, law-like generalizations, theory formation and systematization, in tight contact with the conceptual frame of medical sciences and all the levels of medical education and medical care of the more pressing old problems as well as of the new emerging ones.
7.2. Re-Unification of Clinical Scientific Method for Practice and Research
In the beginnings of the 21st-century the sleeping potential of the clinical medicine research to regenerate firsthand new scientific hypotheses, must be urgently reanimated to be further verified by clinical studies, surveys, trials, and other investigations, and by basic and industrial laboratory, epidemiological and public health investigations. To achieve this multilateral integration and strengthen medical research own internal logic of progress successfully, careful research must be done on its logic and methodological system. The complex link between the two current scientific clinical, surgical and psychiatric investigations and methods, should be examined: 1) the research of a particular diagnosis and prognosis with preventive and/or therapeutic interventions (R&I) in clinical care, individualized in a sick or healthy person and/or in a family of a community --through the present clinical judgment and decision-making methods in the common medical and health care-- by using more quantitative research methods; and 2) the general research since the one case study and initial study of few cases --applying more qualitative research methods at this initial step--, to the pilot study or trial in the design of larger surveys or trials up to thousands of patients, as well as to the study of the theoretical problems, seeking for new concepts, causes and methods of research and development (R&D) of clinical care, in patients affected by one or more diseases or risks and/or in healthy individuals --through the re-flourishing of the clinical judgment again as a scientific method for discovery of generalities too.
The point is not to oppose clinical care practice to clinical care research [131], nor clinical research to laboratory or public health research, empirical methods to theoretical and interpretative methods, qualitative to measuring or quantitative methods, but to reconcile all of them in favor of science and of the patient. This could be made studying the necessary relationships between scientific theories and methods among researches in the clinic, laboratory, and health system, and the interactions and exchanges among their outcomes, coordinated precisely by the principles of the clinical R&I and R&D, to conjoin the others, because only clinical research focuses and works on the whole individual [25]. These results will provide the more robust tool to attract more and train better young generalist and specialist physicians in clinical, surgical and psychiatric research.
Thus, non-mathematical deduction-like inferences from the new principles that could be achieved at least from empirical or low and medium theoretical levels by intuition and induction, in addition to being analytic as all deductions, could also address new ways to suggest high and low level particular hypotheses, at the empirical level, conjoined with the facts. General principles of clinical medicine science knowledge through these unfamiliar analytical inferences, could give new scientific hypotheses that could be tested in a case or groups of patients by R&D, as well as general principles of clinical practice could give new technical hypothesis to improve the quality of care of an individual patient in clinical medicine R&I. These two kinds of clinical science and clinical practice heuristic and creative methods to generate original hypotheses could be probably easier to be computerized than the ones developed to date without these general principles [25].
These ideas about unifying clinical R&I and R&D could be extended to the epidemiological and public health scientific tasks, which work with partial and whole populations of individuals. The point would be to harmonize epidemiological and health programs and management with epidemiological and health research. These ideas seem to be not so adequate for the basic over medical models or technological research laboratory tasks that usually make full-time R&D. Nevertheless, R&I could be accepted partially concerning applied clinical and sanitary laboratories investigations, because they make the research of the preceding and subsequent states of their subjects to the interventions, which are derived from outside the laboratories: the clinic and health service fields. In addition, it can be said that the successes of the R&D in all medical scientific fields are or have to be introduced into medical practice improving the quality of the R&I in the clinic --and therefore as extension in the public health--, from where almost all of them were born at least in a first instance.
A decade ago, "The Goals of Medicine", an international theoretical research project of the US Hastings Center and thirteen countries, in cooperation with the World Health Organization, established priorities for its long-term progress, and stated to do imperatively reforms in medical research [14]. Really, there are big gaps of scientific knowledge and methodology about medical research, which must be filled in. In the world, conjoined endeavors through jumbo projects will have to continue, but in all medical research fields aimed at helping the completely improvement of all medical research. About the first reform, which is to improve medical research using both of the dichotomized medical research paradigms, there has been since 1994, an international theoretical project in preparation called firstly "Human Health", which deals with this matter [25]. Concerning the second reform, to increase clinical medicine, epidemiological and public health researches, besides, the extraordinary laboratory research "Human Genome Project" designed at the end of the 1980ies [16,141,142], and the "Human Brain Project" [143], also is necessary to do other multinational projects in those fields [14], but integrating them hierarchically. For almost 60 years, something has been lacking such as a "Human Health Project" [144-147], as well as a “Human Development Project”, and a “Human Behavior Project”, using the new clinical economics method [1], and the classical and clinical psychology and clinical sociology methods too. And so on, stressing on anthropology, psychology, demography, sociology, social epidemiology and economy, but never forgetting the crucial role of biomedical, genetic and environmental epidemiology and other health sciences too [146,147].
Nevertheless, those efforts will not be enough to satisfy the present and future needs of national, regional, and global medical research, education and care worldwide. This is because laboratory and sanitary researchers cannot make the indispensable research of the dormant huge mass of clinicians, surgeons, and psychiatrists, and personally solve the disease and health problems of the entire person: unattainable top frontier of the laboratory research and essential operational unit and last objective of public health research. The clinic (offices, wards, and rooms) is the research field and place that potentially in any nation and in the world could produce contributions from at least one fifth --20% on average from 10% to 30%-- of the physicians and dentists that work in clinical practice, to improve it. This concept is very important, if it is analyzed within the context of the USA data [130] exposed above. There exists even a better potential for clinical research within university nurses, and other health professionals as psychologists, social workers, nutritionists, technologists, and others, of the world, because almost all of them work in clinics and could contribute even more with research outcomes in regards to improving clinical care too. Therefore, it is very necessary to make also some international or global clinical and surgical research projects as complex as the genome project, but that will probably not require so much high-cost high-technology, but instead more theoretical, logical, ethical, and philosophical integrative thoughts and methods of science.
In this sense, the unity of the health of the human being only could be achieved through a "Human Medicine Project" [146,147]. It could develop a “Clinical Medicine Interface” subproject to rigorously translate and validate those biological, economic, and psychosocial results to practice that come from the basic and public health jumbo projects. It could be interface also to other projects as the Digital Human, Medical Simulation and Training, Virtual Autopsy, the Virtual Soldier, etc. [29]. However, so important will be to fulfill some essential needs of knowledge and methods in the hospital, community center, and office, to develop at least the following own clinical medicine subprojects: “Basic Clinical Medicine”, "Conception of New Clinical Medicine, Surgery, and Psychiatry Research Spaces", "Creation of New Family Medicine Research Spaces" [128], and “Creation of a New Health Classification". The two latter for use in primary general medical care and family medicine –by various classification axis--, according to the phases of the life cycle of the individual and family [25,146,147].
It should take very hard work to unify three of the main dichotomized medical research paradigms: humanism-science, body-mind and disease-health [25], but all medical sciences together will do it. However, simultaneously, the critical mass of clinical investigators has to be increased and better prepared than ever. Working on the re-flourishing of the clinical judgment as scientific discovery method of generalities again, could be the most powerful way to attract more young generalist and specialist physicians, giving them a much better training concerning clinical, surgical, and psychiatric research and practice. Clinical, researchers and his educators must carefully study the experiences of robust scientific training in last decades of laboratory and sanitary researchers. For instance, this could be achieved studying the training programs for basic laboratory researchers applied in the US National Cancer Institute, Oxford Institute for Molecular Medicine [16], and the training for sanitary researchers in the John Hopkins School of Public Health, London School of Hygiene and Tropical Medicine, US Center for Disease Control and Prevention, and so on [7,123].
For some decades, both the US Robert Wood Johnson Foundation in the Yale University School of Medicine and other schools, and the Rockefeller Foundation in some medical schools at home and abroad (like in China in the 1980s), have been strengthening clinical research respectively, with programs to prepare good clinical specialists and clinical epidemiologists to make better randomized clinical trials [7,123]. However, due to all the previous analysis of clinical research weaknesses, the new model of training proposed would have to exceed these important efforts, and be more powerful in order to approach a broader spectrum of ortho-research in clinical sciences through its own initiative. Clinical medicine, surgery, psychiatry, and dentistry research training would have to receive more than the hypothetical-deductive method, Gaussian, Bayesian, and non-parametric statistics, computing, artificial intelligence, decision-making, computer support systems and cost-effectiveness methods, computer simulation; along with clinical trials meta-research and its research ethics. They could receive mainly two handbooks: One of a Unified Medical Research Methodology, and another about a broad Clinical Medicine Research Methodology, in a research training of two to three or more years to obtain with a thesis a Master in Clinical Science (MCSc) and/or a Ph.D. academic degree in Clinical Science, before, beginning or after the generalist or specialist residence training. It must also include mathematics, exact and basic sciences, genetics, anthropology, psychology, sociology, social epidemiology, clinical economy, clinical psychology and sociology, full uses of internet, telemedicine, e-medicine, e-health and electronic-research collaboratory and networks for clinical medicine research, and clinical medicine interface research at a distance, and specially philosophy of medical science, including ethics, ontology, and epistemology. It could be used also modeling and simulation for the research education and training [29]. For nurses, technologists, and other health professionals, the program could be modified attending to their more specific profiles and requirements. Very important would be to include the enhancing of global health with more primary care research on healthy lifestyle through an electronic research collaboration network [55].
An international pilot school or institute, could be established somewhere within some institution, under the direction and coordination of the World Health Organization, with funds from different international sources. This institution could be aimed to research and elaborate didactic materials and educate postgraduates in this new conception of whole medical research process, including the clinic, laboratory, and health system, in their physical sites and web sites; guided by a unified medical methodological system of scientific research, to rescue and strengthen the complete internal logic of progress of medical research and not only of one or two fields. The programs of courses, workshops and conferences, would be very important not only to be taught and studied by clinical, surgical, and psychiatric researchers, but also by sanitary and laboratory researchers, as well as by public health research policy makers and public and private medical research industrial managers worldwide [148].
This school or institute could be the head coordinating center in any country selected, carrying out clinical medicine and public health jumbo projects. Its subprojects could be coordinated with different peripheral centers in other countries through telecommunication means. Later, previous or simultaneously with this experience, it is also possible to set inside or outside of the above institution, another international pilot clinical medicine ortho and meta-investigation school or center, to begin to research, elaborate didactic materials, and prepare clinical and surgical researchers with a more solid background, creative skills [45] and a broader scope than the trialists have today, in order to develop more clinical and medical sciences. The analysis of the results obtained with this trans-methodological research model beginning with the postgraduate programs, should be a guide of how to introduce it into the undergraduate curriculums of medical, dentistry, nursing, technologists, and other health professional students. International exchange through Internet of enough scientific methodological information without high-cost technologies [40,46] could solve many communication problems that would have made such projects impossible to be performed in the past.
The practical application of this unified methodological approach for medium and long-term might become very significant. It could be use along with the present and future separated research methodologies, from the level of the student, scientist, physician, dentist, nurse, technologist, and other health professionals, up to the medical organizations of center, basic, clinical and industrial laboratories, as well as university, nation, region and world. It could be vital for a yearly saving of trillions of days of peoples suffering from maladies, and of hundreds of billions of healthy or useful life years lost by premature chronic diseases, disabilities and deaths, as well as of hundreds of billions of dollars spent worldwide, by the states and private agencies, laboratories and companies, and non-governmental organizations.
8. Conclusions and Recommendations
Clinical medicine is the heart of the humanitarian and scientific practice, research, and science of medicine with the individual human patient. It has advanced very much in two centuries of scientific research. However, clinical medicine scientific knowledge and systems are yet incomplete and partially studied, with many hidden key variables still for discover by the clinical investigators through the old and criticized clinical judgment scientific method. No other clinical method seems now that could substitute by the moment this basic hypothesis-driven method, although many others can and will complement it. The still factual and theoretical lagoons in clinical medicine systems are the reason why up-to-date the clinical investigator cannot investigate anything without the help of probabilistic techniques and statements. New degrees of observation and levels of analysis must be employed for the completion and re-interpretation of medical systems theory in deterministic statements and formulas too. In the future research, the clinical investigators must make use of all the modern theoretical and empirical methods, and utilize all the modern technological instruments of diagnosis and research developed, and have the collaboration of all the derived pre-clinical and post-clinical sciences, and of all the contemporary hard and still soft sciences. It is fair to say that this huge scientific research program was impossible to do two centuries ago.
The clinical investigators will have to discover new ways to solve the body-mind problem created in the 17th century, centering much more their attention in the mind, and not letting it relatively aside, except the psychiatrist, to be able to explain, predict, and handle better the human system. They will have to find by themselves, with much more research in the human physiological and pathological, healthy and sick system, the key hidden variables, which transitory absence have given the mistaken idea to most physicians and scientists since the 17th century: That all human phenomena in medicine had an “irreducible randomness”, which can only be handled indirectly by the statistical inference, and not directly by the clinical medicine inference and even by mathematical equations as any hard science does.
This paper mainly exhorts to link much more the concepts in medicine of clinical research and intervention (R&I) of the patient with clinical, pre-clinical, and post-clinical research and development (R&D) of the same patient or its models; as well as of the empirical and quantitative methods of research along with the theoretical and qualitative ones. It conceives both types of research in the clinic, laboratory, and health system, and in their virtual locations through the information technologies (IT), as related fields and moments of a unique creative process to solve in the last instance clinical scientific problems. This rapprochement across the methods could allow establishing later scientific methodological general principles of medicine. Linking explicitly, the ignored theoretical and interpretative methods along with the empirical highly appreciated technological procedures, is a suggestion. Thus, besides a more complete use of the hypothetico-deductive method, could be used knowledge-driven and data-driven methods, as well as human modeling, experiment, and prediction by computer simulation method. It argues the use of an axiomatic-like method as well. Another proposal is that clinical judgment must flourish again as the general scientific method of medicine, not only for particulars, but also for generals formulating new scientific hypotheses to be falsified or verified further by small and large clinical research, surveys and trials, in individual patients and in groups of patients, as well as by laboratory and sanitary investigations. This would provide a powerful tool to attract more and train better young physicians in clinical research.
The physician clinical investigators, must hear all reasoned criticisms and act in consequence, but must defend the scientific method and scientific clinical medicine foundation from unreasoned criticisms to preserve the highest certainty of the scientific judgments and scientific truths of medicine and objectivity of its practical methods for the benefit of the individual patients. To do this, the clinical investigator cannot hide the theoretical and methodological lagoons that still exist in medicine. He/she must face the criteria that have arisen in non-physicians and some prestigious physicians, assaulting the reason and inviting the flight from science in the medical profession. The wanting and consenting of a setback to a pre-scientific medicine, based on the real theoretical, methodological and practical insufficiencies of this immature science yet is antiscientific. Instead, the physician clinical investigators should try to solve the theoretical and methodological vacuums and inconsistencies, and the practical insufficiencies in the health care that physicians give, in all the medical general and specific specialties. The new physician clinical investigators could have in this humble essay a modest motivation to continue the incessant critical spirit searching and researching for new advances in clinical medicine based on the scientific truth. The best practical rules to contribute to clinical medicine scientific progress are:
1) To study, work, and research very much with the patients and families in their environments, and with the medical and other sciences’ theories and technologies in the weakest medical areas;
2) to learn how to research into the today “normal science” of the scientific paradigms accepted, to be able to research, suggest and promote new shifts of paradigms with new research programs;
3) to do not be afraid of the numberless followers of the existent scientific paradigms who will explain very easily all your scientific doubts and concerns with present research programs;
4) to continue and to do not depress when your critical thoughts and hypotheses are many times apparently not heard and not published as if they were out of the reality or mere dreams;
5) to continue studying from the roots of medicine and discovering new insights, until you learn a better way, from others, to express your arguments and convince the scientific community let the scientific truth to open up step and to leave finally to the light;
6) the greatest scientific challenge in this century continues being since three centuries ago the improvement of the research training and scientific research of the general medicine specialists, and particularly the family physicians in the primary care. This could be an important contribution to the New Enlightenment in this century.
The medium just in clinical medicine research should be achieved, when the pursuit of clinical relevant results by a clinical, surgical or psychiatric investigator, with a more explicit creative and empowered clinical judgment scientific method, retake again the scientific leadership of clinical research. In this crucial task, clinical statisticians, mathematicians, and other scientists must assist them in measuring and in the formulation of probabilistic or deterministic statements, functions, and even equations. This should be possible only when in the new generations of physicians also emerge the partial or even full-time theoretical clinical investigators to work besides the empirical clinical investigators who have worked very successfully with the logic of facts and with partial knowledge since two centuries ago.
Perhaps, it would be possible to create through a special electronic-research network or collaboratory an "International Group for the Reappraisal of the Methodology and Logic of Clinical Medicine Research and Science". It is necessary to increase the medicine doctors' interest, knowledge, and abilities to make good scientific research, no matter if they are generalists or specialists. This is because, a bigger part of the physicians, dentists, nurses, and other health care professionals, are to date the biggest potential mass of “scientists” that world science possesses to face efficiently the still huge health problems of humanity in this 21st century after nine millennium of human history, not completely solved with the more limited “laboratory and public health research forces” up-to-date.
It is also recommended along with very rigorous and integral new training programs of clinical researchers, such as the ones of laboratory and health sciences, the design of theoretical, clinical medicine, and public health international basic jumbo projects, integrating them hierarchically with the human genome, brain, digital human, virtual soldier and civil patient, and other basic projects, through the clinical medicine one.
Acknowledgments
This work is a tribute to six key professors I had. They motivated me to initiate studies on the matters as follows: Since 1964, on the theory and logic of clinical medicine, Doctor Fidel Ilizástigui, Professor of Medicine at our Havana University Hospital Calixto Garcia (trained by our Professors Pedro Castillo and Agustín W. Castellanos); since 1968, on the theory and logic of science by Electronic Engineer Ramón Ventoso, Professor of Physics (trained at Havana University and at MIT, Ma, USA), and by Doctor in Pharmacy and Mathematics Antonio González, Spanish Invited Professor of Mathematics and Statistics, both at our National Center for Scientific Research. Since 1975 on the theory and logic of clinical research, by Doctor on Physics and Mathematics Julio C. Margáin, Mexican Invited Professor of Research Method at Mexican Institute of Public Health; by Doctor in Biostatistics John Fertig, US Invited Professor of Biostatistics at Columbia University, NY; and by Doctor in Mathematics and Medicine Alvan R. Feinstein, US Professor of Medicine and Epidemiology at Yale University, Co.
Related Chapters
Medicine, Science, Philosophy of Science, Theory of Science, Logic of Science, Positivism, Post-Positivism, Basic, Clinical, and Health Sciences, Physiological Sciences, Physical and Biological Sciences, Economic, Psychological, and Social Sciences
Glossary
Science: Any system of knowledge that is concerned with the physical world and its phenomena and that entails unbiased observations and systematic experimentation. In general, a science involves a pursuit of knowledge covering general truths or the operations of fundamental laws. Encyclopædia Britannica
Method: A discipline that deals with the principles and techniques of scientific inquiry. Merriam-Webster Online
Scientific method: Term denoting the principles that guide scientific research and experimentation, and also the philosophic bases of those principles. Definitions of scientific method use such concepts as objectivity of approach to and acceptability of the results of scientific study. Objectivity indicates the attempt to observe things as they are, without falsifying observations to accord with some preconceived world view. Acceptability is judged in terms of the degree to which observations and experimentations can be reproduced. Scientific method also involves the interplay of inductive reasoning (reasoning from specific observations and experiments to more general hypotheses and theories) and deductive reasoning (reasoning from theories to account for specific experimental results). By such reasoning processes, science attempts to develop the broad laws that become part of our understanding of the natural world. Science has tremendous scope, however, and its many separate disciplines can differ greatly in terms of subject matter and the possible ways of studying that subject matter. Encyclopedia Encarta
Baconian method: Methodical observation of facts as a means of studying and interpreting natural phenomena. This essentially empirical method was formulated early in the 17th century by Francis Bacon, an English philosopher, as a scientific substitute for the prevailing systems of thought, which, to his mind, relied all to often on fanciful guessing and the mere citing of authorities… Encyclopædia Britannica
Hypothetico-deductive method: Procedure for the construction of a scientific theory that will account for results obtained through direct observation and experimentation and that will, through inference, predict further effects that can then be verified or disproved by empirical evidence derived from other experiments. Developed by Sir Isaac Newton during the late 17th century. Encyclopædia Britannica
Axiomatic method: In logic, a procedure by which an entire system (e.g., a science) is generated in accordance with specified rules by logical deduction from certain basic propositions (axioms or postulates), which in turn are constructed from a few terms taken as primitive. These terms and axioms may either be arbitrarily defined and constructed or else be conceived according to a model… Encyclopædia Britannica
Medicine:
The science concerned with the maintenance of health and the prevention, alleviation, or cure of disease. Encyclopædia Britannica
Surgery: Branch of medicine that is concerned with the treatment of injuries, diseases, and other disorders by manual and instrumental means. Surgery basically involves the management of acute injuries and illnesses as differentiated from chronic, slowly progressing diseases, except when patients with the latter type of disease must be operated upon. Encyclopædia Britannica
Philosophy of science: The study, from a philosophical perspective, of the elements of scientific inquiry and of their validity. Taken broadly as the progressive improvement of the understanding of nature, the intellectual enterprise of science originally formed an integral part of philosophy, and the two areas of inquiry have never finally separated. Encyclopædia Britannica
Medical Technology: The term technology began to define well the double essence of the practice of medicine in its progress, first as an applied art, and at the same time later as an applied science too, using knowledge, materials, tools, techniques, and becoming further dependent of the advances of applied medical and allied sciences, to increase the efficiency of medical work.
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Agregar
Murillo H, Reece EA, Snyderman R, Sung NS. Meeting the challenges facing clinical research: solutions proposed by leaders of medical specialty and clinical research societies. Acad Med. 2006 Feb;81(2):107-12.
Biographical Sketch
Dr. Rodolfo-Javier Stusser-Beltranena is a baby boomer physician trained since 44 years ago as professor and researcher on top basic science labs, on internal and general medicine practice in urban and rural centers, and on public health, biostatistics and informatics in Havana University (HU). He founded the Basic and Preclinical Sciences Institute (1962), Scientific Research National Center (1968) of HU, Health Development Institute of MOPH (1976), Clinical Research Center (1992) of West Havana Scientific Productive Pole, and assisted the Plaza- (1990) and the Vedado (2002-) Community University Polyclinics to become Science and Technology Units. He has 38-year studies on the logic, forecast, policy and program of clinical and population research and trials, health services research on infant and maternal, cancer, myocardial infarction and stroke preventable mortality, global health research, and other matters, in national institutes, hospitals, community centers in Cuba, Nicaragua, and with East Europe Comecon 1969-1989, PAHO/WHO/ 1988-2006. 43 years teaching students, residents, researchers & professors in neuro- and other physiologies, semiology, medical research method & statistics, epidemiology and informatics. He was designer and founder of the laboratories of medical research methodology for the 15 Cuban institutes of health and hospitals in 1977, and to community centers in 1990, and teaching pioneer in the National Cancer Institute of the logic of clinical and epidemiological research and trial at Havana University 1977-2006, as well as at Managua University and PAHO/WHO Office 1988-1990. From 1970-1987, he supplied scientific evidence to reorient the scientific R&D policy in some national institutes of health with emphasis then in basic R&D, toward more clinical epidemiological and technological research, according to the scarce funds of his developing country. His Ph.D. degree-thesis results: "Five unified scenarios for cancer research, prevention and control for Cuba 1985-2000" (first in Iberian America), were applied in the planning of three MOPH programs: "Anti-Cancer Struggle” and “Oncology Specialty" 1987-2000, and "National Health System's Objectives, Goals and Directives 1992-2000".
Dr. Stusser is the first Cuban International Member of the American Academy of Family Physicians, and member of the International Societies of Clinical Biostatistics and Internet in Medicine. He is founding Partner of the WHO Alliance for Health Policy and System Research, and since 2000 Adviser/Lecturer at Havana to US People to People Ambassadors Professional Program, Sam Nunn School of Foreign Affairs Georgia Tech Institute, within other US organizations, doing lobby work to restore the US-Cuban scientific research collaboration initiated 250 years ago. He retired in 2006 from his state job to make independent studies.