Abstract
The simultaneous systematic analysis (SSA) approach, emanating from the novel achievements in science and technology, is targeted to provide a broad insight into the human body physical and mental functioning in various surroundings. Thus it paves the way to personalized, preventive and predictive medicine. The goal is to form an ongoing collaborative research and development platform focusing on the micro and macroenvironmental factors of the complex human functioning. This approach aims to build an open, innovative, systematic joint effort, combining and sharing all acquired knowledge and expertise among the leading professionals in all relevant areas of science and technology, while reducing technical, conceptual and formal barriers. The CHEST methodology (converging humanities, education, science and technology) will be utilized, as an innovative meeting point, enabling open and coherent discussions among all stakeholders from all relevant disciplines. The SSA approach is complementary and fully aligned with the partitioned research, creating a well-structured joint effort, ongoing R&D sharing and borderless discussions among the academic research, government, regulatory agencies, industry, and the public. Bringing on board all stakeholders including young students, could provide innovative outcomes and new regulations adjusted to the new era. This review study focuses on the cardiovascular diseases (CVDs) diagnosis and treatment case study, as CVDs accounts for about one third of human morbidity and mortality and is a main driver in the biomedical and drug industries. The American Heart Association (AHA) in its 2020 published health goals reflect a similar attitude and thus provides strong support to the SSA approach. It is the authors’ contention that applying the SSA approach could provide the essential comprehensive insight into individual complex functioning over time and place. Thus, it would enable responsible personalized, accessible healthcare and yielding major economical and sociological impact on society.
Introduction
The remarkable achievements of science and technology, enabling a broader insight into the individual physical and mental functioning in their surroundings, is ushering a new era of well-being and epochal evolutions in healthcare. The new affordable technologies such as high throughput diagnostic platforms, big data analysis, major gene and biomarkers discoveries and advanced imaging have led to targeted diagnosis and treatments. Yet, in spite of all these, there is an urgent need to conduct strategic joint efforts and innovative approaches in order to tackle the barriers and un-resolved healthcare concerns in cancer, cardiovascular diseases (CVDs), neurodegeneration, infectious diseases, etc. Thus the convergence of knowledge, data and all identified factors, at the micro-and macro-environment level could provide the essential platform translated into healthcare for all based on the principles of predictive, preventive, participating and personalized medicine (PPPPM) (1).
A simultaneous systematic analysis (SSA) approach is presented to bring together all relevant areas of science and development towards ongoing discussions, sharing and converging all available knowhow and technologies, while bridging the gaps and thus providing the broader possible insight on the human functioning in its surroundings. The goal is to identify, extract and define all features, such as the biochemical, biophysical and genetic tools, together with the psychological, behavioral and environmental aspects such as climate, culture, and community, all integrated into the computerized world (1, 2). This joint systematic effort between all relevant areas of science and technology, focusing on a scientific or medical dilemma, could provide the broad essential insight on human functioning translated into a reliable, responsible and personalized medicine.
The focus of this review study is on the CVDs – diagnosis, treatment and prevention – as a case study. The social complexity of CVDs is shown, for example, through the higher risk and rate of mortality among single men with weak social networks compared to married men or single women (2, 3). The broad environmental aspects are clearly seen through the example of emigrants’ populations – South Asian and Indian/Pakistani immigrants adopting the United States-born patterns of CVDs within one generation (4, 5) potentially through adopting the American diet, lack of physical activity, etc. Thus, the first step of the suggested SSA approach is to harvest, combine, analyze, converge, evaluate and interpret the existing and newly derived knowhow into a well-structured operational, affordable knowledge base.
As the SSA goal is to “rethink the segregated paradigms”, an integrative systematic effort will be established utilizing the CHEST (converging humanities, education, science and technology) methodology, providing an open and innovative meeting platform among the various areas of science and all stakeholders, to share and discuss all knowhow and technologies while reducing conceptual and formal barriers. Creating a common ground among all stakeholders from academia, industry, regulatory agencies, governmental policy makers and patients’ advocacy groups is essential to ensure the responsible and productive translation into clinical and medical practice, fully adapted to the individuals’ complex functioning in their surroundings and thus enabling PPPPM (1).
The SSA approach is based on the numerous achievements in science, technology and industry such as the human genome project and the converging technologies approach, core enabler to PPPPM, conceived through a simultaneous approach utilizing diversified tools, advanced technologies and fundamental research (5, 6). The “Converging Technologies” National Science Foundation (NSF) initiative, first discussed in 2001, suggested the combination of nanotechnology, biology, informatics and cognition (NBIC) (7). It gained world-wide support, involving huge governmental and private investments in many initiatives. These initiatives yielded the establishment of new interdisciplinary policies and institutes, while changing the paradigms of research and education and contributing numerous products that were brought to the markets. In 2009 the National Nanotechnology Initiative led by the NSF, together with other US governmental agencies, invested about $1.7 billion and reaching final product market of the value of $92 billion in the USA alone. Worldwide the final product market value reached the level of $254 billion in 2009 based on $7.8 billion worldwide governmental investments (8). Based on these remarkable achievements, the NSF presented on Dec 2012, the CKTS (converging knowledge, technology and society) approach reflecting the series of workshops held all around the world. The “holistic approaches to wellness and human development" is a major recommendation for promoting scientific progress (7).
Why focus on cardiovascular diseases (CVDs) – challenges and opportunities
CVDs account for one third of human morbidity and mortality (2 million deaths per year only at the EU, with estimated annual direct cost of 110 billion (5, 9)) and thus there is much anticipation for its large marketsize and it is of great interest to the biomedical and drug companies. The very high morbidity prevails although mortality from CVDs declined by 31.9% in the last decade (5, 9, 10).
The high complexity of CVDs is attributed to complex heart structure and function, the ramification of the vascular system and the dimensions of the endothelial system, now considered as the largest hormonal system of the human body (11). The cardiovascular system is also affected by nutrition, immunity, hormonal control, removal of waste and by gender, ethnicity, climate regions and life style (5, 9, 10). It is influenced at the earliest stages of life as reflected by the special guidelines regarding mothers who experienced gestational diabetes, preeclampsia and intra uterus growth restriction (IUGR) that are CVDs risk factors for mothers and their newborns. Another influence is generated by the men sperm that undergo epigenetic changes expressed by DNA methylation that may affect their progeny through at least three generations after suffering profound poverty and stress (12, 13). Furthermore, there is a need to evaluate the lifelong changes in nutrition, obesity and physical activities during childhood and adulthood along with the menopause cycles, aging, marital status (couple or single) – all required for evaluating cardiovascular health and pathophysiology (5, 10, 12, 14). Thus, a systematic analysis, as presented at the SSA approach, enables the convergence of all these aspects and is essential for a better understanding, improved prevention and advanced therapeutics in CVDs.
The simultaneous systematic analysis approach gained formal support
This SSA approach gained strong support from the 2012 to 2014 published cardiovascular health recommendations of the American Heart Association (AHA). Aiming “to improve the cardiovascular health of all Americans by 20% while reducing death from CVDs and stroke by 20%” (5, 9, 10), the AHA suggested a holistic approach and presented four behavioral preventive metrics and three biochemical metrics to assess people cardiovascular health. Compliance with these seven metrics among non-drugs users defines the “ideal”, “intermediate” and “poor” cardiovascular health conditions as evaluated through personalized algorithms tailored to age, ethnic and gender differences. The AHA implementation plan is in accordance with the American Association for the Advancement of Science (AAAS) approach (15, 16). The AHA plan addresses: 1) personalized lifestyle adjusted to age, gender, ethnic, urban and demographics; 2) community level to encourage, facilitate, and reward the healthcare providers to improve access to physical activity trainers, dietitian’s consults, anti-smoking clinics, bariatric surgery, etc. and 3) population level targeting lifestyle through school education programs, workplaces social benefits, local communities’ events and regional government campaigns extending throughout the nation (9, 15, 16).
Given the central role of the cardio-vascular system in the human body and its strong lifelong functioning, both the AHA recommendations and the SSA approach support the need to review CVDs throughout life span from fetal life, childhood, adolescence, adulthood, pregnancy up to menopause and aging. The shift from general disorders treatments towards the personalized and prevention approach with special emphasize on individual responsibility is crucial for the next breakthrough in CVDs (16, 17).
The simultaneous systematic approach work plan
The SSA approach provides a practical platform for ongoing borderless convergence and sharing of captured knowledge and technologies between all relevant research groups and stakeholders focusing on a specific disease/dilemma. The goal is to identify, evaluate interpret and combine the acquired knowledge and information of the complex human functioning in the surrounding. That includes the micro environmental physical, chemical, biological features and the macro environmental features, such as the broad cultural and technological aspects and their adverse impact on family, sociology, and communities and up to the environmental affects (climate, radiation, light, water, magnetic, wind waves, etc.). The goal is that this structured converged knowledge and technology could provide a comprehensive insight on human functioning in the surrounding enabling translational medicine and responsible personalized healthcare (Figure 1).
The SSA approach – work flow.
The human being and the surrounding as one functioning system.
To enable and achieve these cross-disciplinary effort the CHEST methodology will be utilized to create a common ground and enable open and fruitful discussions among professionals and students from academia, industry, governmental authorities, patients groups and the public, while bridging all concepts, languages and other disparities (Figure 2) (18).
The SSA Approach applied to CVDs – operational flow chart: multilayer interactions between diverse disciplines.
Meetings methodology: CHEST – converging humanities, education, science and technologies.
The advantage of the SSA approach can be envisioned, for example, through the analysis of anti-hypertensive drugs. Between the years 2007 and 2010 hypertension affected 33% of adults over the age of 20 in the Western world with annual Western World spending of $118 billion. However, only 53% of the hypertensive patients are controlled and regulated by the numerous existing drugs (5, 10). Unexpectedly, given the market potential, the industry is reluctant to finance future investments due to the lack of tools and resources needed for patient stratifications and sub-population identification, essential for targeting a novel anti-hypertensive drug. The SSA approach could shorten the lead time towards new anti-hypertensive personalized drugs through a systematic joint effort yielding the identification of new factors, new biomarker and monitoring devices and thus could overcome the existing barriers and failures (19).
The first stage of the SSA approach
The first stage of the SSA approach is to harvest, converge and utilize all relevant scientific achievements, knowledge, information and technologies to be organized and structured in multidimensional, easily accessed innovative modules (Figure 3). The goal is to enable sophisticated handling, inquiring and interpretation of the databases utilizing all existing and newly developed targeted tools and technologies to reach, for example, high resolutions imaging and unprecedented scales of precision and thus providing new insights (20). Furthermore, sophisticated analysis techniques and data mining tools will be utilized to enable multisource, multilevel combined analysis and rule discovery scheme (such as WizWhy, etc.) (21). The accumulation and analysis of the existing databases, by itself may lead to new understanding of mechanisms and new insights that could be translated to refined and personalized diagnosis and treatment.
The envisioned integration and possible outcome at all levels, from the molecular to system and up to the population.
Reviewing the scientific and medical research of CVDs, in view of the first stage of the SSA approach, including knowledge and data collections and analysis, present a 30% reduction in mortality in the two last decades and the 10 years increased longevity. These achievements are broadly attributed to interventional angioplasty and the use of novel drugs with a proven clinical and statistical role in patient survival and recovery (5, 9, 10). The drug coated stents (DES) are among the drug-device innovative products carrying the promise to recovery from major CVDs. The comparison to bare metal stents (BMS) shows lower restenosis by 65% but at higher cost and a longer use period of anti-thrombosis drugs (22). The SSA approach could be embedded, in this case, through the collection, analysis and modeling of all individualized data related to the DES and BMS to provide optimizing personalized guidelines for matching the anatomical and biochemical personal features, patient age, life style, environmental impact, social support, etc.
The second stage of the SSA approach
At the second stage, the SSA approach suggests an ongoing borderless multi-disciplinary research benefiting from all captured, converged and analyzed data and knowledge acquired at the first stage, through the embedding of all area of R&D (Figure 2). The various areas of research may include physiology, biology, anatomy, pathology, hormonal regulation, etc., positioned within the context of culture, community, ethical, psychological, and environmental aspects. The simultaneous ongoing sharing of knowledge, findings and technologies between all professionals in the various areas of research could, by themselves, yield new understandings and innovative achievements. The systematic involvement of the different scientific area tackling a common barrier could provide creative research based on different approaches, prospective, concepts and tools transferred from one area to another. Furthermore, bringing on board the industry, the patients associations and the public – could provide new insights, present new needs, malfunctions and major issues to deal with. That includes the legal and regulatory authorities that could benefit from the exposure to professional information and thus shorten the lead time towards responsible, well-controlled and managed healthcare. Involving the ethics students and professionals along with other humanities students and opinion leaders, at the basic science levels, could improve the understanding of the whole process and thereby reflect the delivery of reliable, responsible and accurate message to the public.
The advantages of the SSA approach can be demonstrated when one reviews the examples for treating the ventricular fibrillation (Figure 1). Doctors have to take an holistic approach and instead of focusing on preventing embolism, or control the heart rate or maintain/recover the heart rhythm, they should view the patients in a broader view combining drug based therapy, pulse conduction control through open heart surgery, angioplasty or ablating ectopic bursting (23).
The progress in CVDs research is fully aligned with to the SSA approach. The innovation in angioplasty, heart surgery, valve replacement, ablation technologies or in the use of biomarkers such as troponin, are all translated into life-saving and the establishment of novel “gold standards” in diagnosis and treatment (24, 25). Introducing multiple biomarkers and the use of point of care may accelerate current diagnostic protocols for patient assessment after myocardial infarct (MI), coronary heart diseases (CHD), and other CVDs and for applying preventive method of dietary, physical activity and other aspects of personalized involvement. Incorporating these approaches into the computerized world through cell-phone based training and health monitoring, for example, could yield better control, shorten lead time and as a whole improved diagnosis and treatment (26).
CHEST – converging humanities, education, science and technology
At the core of the SSA approach are the open, borderless ongoing collaborative efforts among all research groups, focusing on a specific disease, sharing simultaneously and systematically all findings, while reducing barriers and constrains. The CHEST methodology provides the enabling platform for multidisciplinary discussions and helps to create the common ground between relevant professionals from academia, industries, policy makers, regulatory agencies and patients’ organizations. The goal is to create a structured meeting point enabling an open innovative dialogue between all relevant areas of science and technology in a structured well-documented procedure, while tackling real scientific barrier or question and/or focusing on a specific disease (18). These discussions would be secured, guard participants privacy and be distributed and/or published upon the signed agreement of all stakeholders. The CHEST methodology encourages bringing on board top scientists as well as young students from the various sciences faculties and other stakeholders groups, to focus on one topic while bridging all the gaps and barriers. Such gaps include differences in research and development concepts, professional languages, various R&D cultures, academia and industry different viewpoints, etc. The time consuming aspects of peer review and journal publication policy as well as the intellectual property registration process is another barrier, already raised in 2011 at the AAAS meeting in the white paper “The Third Revolution: the Convergence of the Life Sciences, Physical Sciences, and Engineering” (26). Solving these issues could ensure the active participation in CHEST of the best contributors, while harvesting and exploring all updated knowledge through an open borderless discussion all the while considering public interests and regulations as well as industrial and patients’ interests. Applying CHEST methodology in the SSA approach is essential to enable fundamental and affordable PPPPM. Reducing the disease prevalence is just one possible outcome that would have significant impact on mastering the diseases as well as on the pharmaceutical industries and thus on the wellbeing of world citizenry (1).
The emphasis on CVDs nowadays is shifting from advanced treatment into prevention including a major effort to reduce the new patient pool derived from the obesity epidemic. Obesity affects 34.6% of adult men and women in the USA. Overweight children increased from 4% in 1979 to >31% in 2010 (5, 10, 15) 16.9% defined obsess [(body mass index >30 kg/m2, cholesterol level >240 mg/dL). The age adjusted prevalence of the cluster of metabolic syndromes is ∼34% of which 8.3% are diagnosed diabetes mellitus alone, along with many undiagnosed and pre-diabetics (5). CHEST can provide the meeting point platform to deal with the new CVD patient pool, bringing together clinicians, R&D professionals, policy makers, the education system and the public to fight obesity, smoking, to reduce the new patient pool for CVDs, especially among children.
The SSA approach, envisioned as a matrix
The suggested SSA approach through its systematic and simultaneous joint research efforts could be envisioned, for simplicity and operationally, as a matrix incorporated to analyze and share the various research groups findings (columns) evaluated (in the case of drug efficacy, for example) through the comparison between the healthy population and patients who were diagnosed but not treated, asymptomatic individuals who have early borderline physiological parameters that indicate predisposition and treated patients (rows) (Figure 4). The crosscuts among the various factors in each classified group (row) and at the same time in between the three layers (rows) for a specific disease (matrix), could provide valuable information that is not usually visible and shared between scientific groups and/or clinicians. Thus, the drug efficacy, in this case, could be evaluated in a broad spectrum and interplay to optimize the drug usage, reduce side effects, shorten the lead time and thus lower the development resources and costs. Normally, the clinicians would focus on their specific areas of expertise and mainly deal with diagnosed patients. Due to practical reasons, they would not compare the healthy, diagnosed and treated individuals.
The SSA Approach applied to CVDs: The Matrix Illustration.
The simultaneous systematic analysis approach – matrix components that outlines the ongoing systematic joint research and sharing efforts – micro and macro environmental research.
The matrix approach could be applied to a specific disease and/or symptom or to a family of diseases, comparing indicators, markers or side effects, and assess familial aspects of the various diseases. The goal of this matrix approach is to provide the best possible and accurate insight based on correlations and comparisons, through the intersections cells, between various disease levels revealing all diversified effects and factors, both known and newly discovered as well as to identify primary causes and develop effective prevention (18, 26).
The comprehensive matrix approach could be envisioned as a supportive management aid to harvest and follow up the joint collaboration between the relevant researches, experimental groups and industries. It could help structuring CHEST discussions and support the continuously tracing and sharing of the ongoing research and technologies observations and outcomes. Integration of social and psychological tools with pharmacological interventions, considering the immunological, genetic, pathological and physiological pathways as well as the bio-informatics tools to study cell therapy and immortalized cell lines (7), could provide the essential insight towards valuable solutions for targeted treatment and personalized medicine, thus shortening the lead time and reduce the costs towards targeted safer personalized medicine. For example, directing the choice between tPA and streptokinase according to the selection of the polymorphism of the Cys242Thr mutation of the p22phox gene within the first 90 min after a stroke in the context of ethnicity diversity (Asian versus Caucasian) (27).
Furthermore, applying comprehensive and sophisticated data analysis tools to all the captured data in the matrix could provide accurate profiling of the CVD patients thus refining therapeutic index and tolerability for the clinical use. To provide an accurate and sensitive insight, as required for personalized medicine, multilevel combined analysis tools are needed capable to analyse big-data sets as well as small data sets (including many parameters with few repetitions, records). The need is for rule discovery algorithms enabling a multilevel, multisource combined analysis of mixed datasets (numeric, categorical, images, genetic, etc.) analyzing the data as is without any data modification or adaptation such as normalization. The WizWhy data mining algorithm (21), as an example, handles missing values, identifies unexpected cases and rules (outliers) and provides predictions. Together with other analytical tools, it could be combined in a voting scheme providing broad and accurate insights at all stages of clinical trials. Furthermore, in cases of multiple hypothesis and comparisons the false discovery rate method could be applied to correct and to accommodate for primary and secondary end points yielding greater power and control the family-wise error rate that is mandatory in drug registering experiments (28). The systematic contribution of all professional partners and stakeholders including the ethics, regulatory and public guard, would ensure the reliable and supervised process at every stage including managing the clinical trials and pharmacovigilance processes. Thus the SSA approach suggests an innovative well managed and documented approach targeted to provide the short lead time towards responsible personalized medicine to all.
The NanoAthero EU project
Nanomedicine for target-specific imaging and treatment of atherosclerosis
The NanoAthero EU Project (FP7 NMP) is fully aligned with the SSA approach in the way the research is conducted and managed. Using non-invasive multimodality means, the project utilizes the nano-systems to encapsulate and carry imaging contrast agents to highlight vulnerable plaques with a high risk of rupture and detachment into the blood circulation. The nano-systems rely on their mobility and small size to reach affected regions that are otherwise un-accessible while balancing between local efficacy and system safety. For the nano-system drugs, the technology enables drug encapsulation and their slow release to early stage thrombus or fragile plaques that are about to be detached from the vessels’ walls thereby generating a preferred therapeutic index within a confined region as compared to slow releasing drug coated stents (29) and relying on their preferred mobility and small size. The consortium (16 partners from 10 countries across Europe including research institutes, small enterprises and pharmaceutical corporations) is evaluating a battery of 12 nano-carriers and 18 targeting agents. It aims to develop the four nano-systems to treat and image the build-up of plaque in arteries with ‘vulnerable’ plaques and blood clots (thrombus) that are both not suitable for current treatments due to severe side effects.
Modeling and sophisticated analysis tools will be applied to test animal models and then further extended to clinical trials in human. All analysis will be regulated by ethics principles and risk analysis to ensure safety, and responsible medicine. The SSA approach and the CHEST methodology are utilized to create a meeting point among all partners regarding R&D, ethics, education, training, risk analysis and dissemination issues including preclinical evaluation of the diagnostic and therapeutic systems and clinical investigation of patients at high cardiovascular risk for the specific disorders described above. It is anticipated that over the next 5 years the consortium will be able to offer medical solutions to a sub-population of people previously not treated, with special focus on prevention, efficacy and safety while reducing side effects and shortening the time to market.
Analyzing the SSA approach through the case of statins
Statins, the cholesterol reducing drug family, were discovered over 40 years ago but introduced after the development of the cholesterol measuring devices to determine 200 mg/dL and below. Statin use in treating CVDs increased longevity by 10 years and reduced mortality by 27% (5). However, statins use has now expanded into the prevention of CVDs among patients with hypercholesterolemia, who have not yet developed atherosclerosis (31). This shift requires additional food precautions, as it turns out that some unexpected food ingredients, such as grapefruits, are toxic to statin users who have to avoid them (30).
Statin treatment is personalized, based upon cholesterol level, overweight, family history, diabetes mellitus, smoking, physical activity, high blood pressure, high salt diet, stress management and poor general health. Recently, new methods were introduced including Doppler and imaging to assess the narrowing blood flow to the neck, arms or legs arteries. However, the SSA approach is necessary to involve additional elements to optimize statin personal administration. The lack of biomarkers for statin personal matching is considered as the biggest waste (∼50%) of healthcare cost due to the trial and error in drug prescriptions (31) and elevating drug dose was found inferior to drug replacement. The SSA approach is in full compliance with the AHA approach trying to combine all physical factors with macro-environmental factors such as climate, community and social support to improve the safety profile of statins.
The shift towards preventive use of statins brings to the forefront the safety aspects of life long treatment that has not been examined in clinical trials (31). A recent meta-analysis ranked simvastatin (Zocor) and pravastatin (Pravachol) on the favorable profile of safety, particularly at low-to-moderate doses. However, long-term statin use in post-menopausal women increases the risk of developing myopathy, rhabdomyolysis, myalgia and cancer. Patients with bipolar mental diseases (such as schizophrenia) who are treated by the new anti-psychotic drugs face additional concern as they need higher doses of statins to fight the augmented cholesterol level contributed by new anti-psychotic drugs (32). As these stressful patients mistrust any health care service, they are often late to seek help and fail in drug compliance. As a result, they are often prescribed with the higher drug doses, and are exposed to the most dangerous side effects (31, 32).
Nowadays there are new monitoring devices such as EndoPat providing independent measures for evaluating the risk for atherosclerosis in non-symptomatic patients in addition to the patient’s BMI, smoking, and cholesterol level (33). Sophisticated analysis tools and multi-parametric algorithms are necessary to converge and analyze all captured data and to evaluate all parameters and risk factors to optimize personalized statin use as offered by the SSA approach involving all education and communication pathways, professional meetings and public tracks: web sites, feedback reports, industrial interest groups, etc.
The envisioned outcome
The SSA approach provides a flexible platform tailored to enable systematic joint collaborative efforts’ among all stakeholders focusing on CVDs. The joint collaboration platform includes capturing and analyzing all the relevant knowledge, data and information derived from all sources, followed by ongoing open discussions to gain a comprehensive insight on CVDs. The captured data include demographic aspects (ethnicity, age, gender), climate factors (humidity, dryness, high altitude), behavioral aspects (smoking, physical activity, or health diet) and other factors correlated to morbidity and influencing disease treatment. The flexible structure of the SSA encourages the utilization and combination of all advanced technologies, under tight ethical and regulatory rules, including smart phone (34) and sensors for ongoing capturing and monitoring as well as learning machines which refines their outcome and predictions during usage. That is in addition to all advanced crystallography, high throughput chemistry, pharmacokinetics, proteomic, genetics, advanced screening, etc. All technologies are implemented to gain further innovative insights that can be applied and translated to medical devices, targeted treatments and drugs.
The envisioned outcome of individual/society/medical treatment could be visualized through the multilayer analysis, applied to drug discovery, development and delivery, as described in Figure 4. The matrix presents the applied joint effort of the various research groups to verify, evaluate and compare the diagnosed and treated patients, the diagnosed but not treated patients, the asymptomatic individuals and the healthy person (Figure 4). The purpose is to identify the major factors through the various points of research and expertise and thus evaluate and drug efficacy and side effects expressed through the four groups. The optimized efficacy derived through the capturing and analysis of all factors may impact the pharmaceutical industries and thus reduce drugs expenditure and as a result provide affordable healthcare to wider segments of the populations including developing countries.
The embedding of all areas of science in the SSA approach including environmental, nutrition and community aspects could be justified and applied to the CVDs following cases. Patients diagnosed as being at early stage could be offered vitamins, vegetable and fruits rich diet, while overcoming safety issues (35). However, when the indicators reach higher levels, the patients will need to use anti-thrombotic drugs (36).
The traditional anti-coagulant drug Coumadin requires a repeated weekly blood test to control side effects, which is cumbersome for patients and the health care system. These difficulties gave rise to the later development of three oral anti-coagulant drugs in the hope that they would prevent venous thromboemic events in adults without the need for bi-weekly testing (37). Their advantages are mainly to patients undergoing elective hip- or knee-replacement surgery, and in stroke and embolism prevention in adults without major risk factors. Recent studies also revealed the potential role of these new anticoagulants for the prevention and treatment of venous thromboembolism in cancer patients (38). However, the British Ministry of Health recently issued a drug safety alert related to counter prescription of these drugs due to major impact on the gastro-intestinal and other systems (http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON322347).
The SSA approach offers an open sharing research approach through the drug development process yielding further understanding regarding the drugs broad functioning and thus provides accurate, well-defined guidance to drug usage, optimizing safety and efficacy, and thus ensuring responsible healthcare and balanced personalized clinical services (39). Applying the described SSA approach to CVDs could reduce the drugs lead time to market and increase the efficacy, thereby benefiting all parties. Accordingly, industrial companies would emphasize and value the SSA approach involving monitoring devices and tests evaluated in open discussions to stratify the sub-groups that can benefit the treatment along with means to monitor patients’ improvement while using the drug (Bryant A. Beyond selling pills – Fix the problems and not just the symptoms. 2011. http://www.nytimes.com/2011/10/09/business/joseph-jimenez-of-novartis-on-finding-the-core-of-a-problem.html?pagewanted=all&_r=1&).
It is at the interest of all stakeholders, involved in CVDs, to join all professionals and technological forces, while combining all sources, to optimize the drug developments process including specificity or sensitivity. The goal is to bring on board smart technologies and devices to better stratify patient selection for clinical trials, improve the impact of drugs over placebo while reducing the required effective dose and side effects. Among smart devices that could make the change one may list diagnostic high throughput microchips (40), minimally-invasive electrochemical and glucose biosensors (41), drug releasing biopolymers (42), minimally-invasive vogues and visceral nerve stimulators (43), next generation miniature pacemakers, wearable heart beat and blood pressure monitors (44), GPS associated telemeters to integrate physical activity (45), smart phone applications for physical activity and calories consumption tools (46), among others. These computer-based smart devices enable matching between patients and methods of treatment in order to reduce expenditures, raise efficacy and potency, and thus minimize malpractice law suits and supports medical insurance companies. The time is right for the proposed SSA approach taken by diversified R&D disciplines, computer manufacturers, the pharmacy industries, governments and public organizations for the enhancement of social network power, public awareness and education towards responsible and affordable medical innovation, accessible for all.
Conclusion
It is our contention that science and technology have reached the stage of maturation towards a borderless, structured, joined research effort, in parallel and fully aligned with the partitioned scientific research. The goal is to join all forces among the various areas of science and technology and all stakeholders towards systematic and borderless sharing and discussions of all knowledge, data and technology related to the human micro and macro environment. That is to provide new understandings and comprehensive insight on the human complex functioning in its surrounding, translated to better diagnosis and treatments. The SSA approach aims to provide the targeted platform motivating all stakeholders in academia, industry, government, regulatory agencies, patient groups and the public to join efforts in a systematic structured dialogue focusing on a specific disease or scientific dilemma, to the benefit of all. CHEST methodology will be utilized to enable and encourage the open discussions and sharing, while reducing technical, formal and mental barriers between the various areas of science and stakeholders and thus creating a common ground between all partners. Involving the humanity studies, ethics professional and students as well as the government and regulatory representatives, at the basic science research level, including exposure to lab work, could yield broad understanding of the various phenomena and thus an accurate responsible message conveyed to the public. Furthermore, the capturing, structuring and sophisticate analysis of all relevant and aggregated knowledge, data and information in an open and handy form, suggested at the SSA first stage, is a great step forward by itself, as it could reveal new correlations, yield new understandings, the support or decline of current perceptions and laying the stable common ground to further joint research and discussions, translated and transferred into advanced research and industrial applications.
These joint efforts are for the best interest of all stakeholders in the various research and application areas, and might yield scientific breakthroughs, identifying innovative drug targets and development of novel medical instruments in relatively lower resources. Inviting the young students to take active part at the open sharing and discussions, while applying CHEST methodology, could provide innovative and creative “out of the box” thinking, leading to unpredicted outcome while giving rise to renaissance future scholars. The inherent flexibility of the SSA approach enables the systematic online capturing, harvesting, monitoring and ongoing control of any relevant data sources and knowledge through smart devices, mobile phones, remote sensors and other sophisticated and computerized technologies. At the same time the enabling of virtual structured and documented web meetings parallel to the physical ones, could engage remote participation, additional insights and added value. Hence, it is crucial that the ethics professionals, the regulatory agencies, the government representatives as well as patients’ communities will take an active part in the SSA approach providing the optimized protection and guidance, upon their comprehensive insight, especially regarding remote sensing, mobile control, content protection, etc. Thus, in order to optimize the application of the SSA approach and to leverage an open ongoing sharing and cooperation among all participants, some technical and formal barriers have to be removed. For example, the peer review and publication time consuming process as well as the intellectual property (IP) registration, as was already stated at the AAAS 2011 meeting by Alan Leshner, CEO of AAAS and executive publisher of Science (http://www.aaas.org/news/releases/2011/0118convergence.shtml). Furthermore, the education system in general and the academic education in particular, have to ensure the optimized study curriculum in the various areas, enabling broad interdisciplinary studies, while keeping the expertise and specificity levels.
The focus of this review study on the CVDs provides numerous examples of the possible impact driven by the interplay of all identified factors inside the human body and the surrounding factors, as suggested by the SSA approach, yielding reduction in lead time to product and costs. The comprehensive sharing and professional discussions involving all scientific areas and stakeholders, based on all the captured knowledge, could be utilized towards optimized translational medicine and thus responsible preventive and predictive personalized medicine for all. Various practical steps have already been taken throughout the world, along the same lines with the SSA approach, including the establishment of the bio-banks for clinical trials by the European Clinical Research Infrastructure Network – ECRIN, the NSF series of workshops of the World Technology Evaluation Center (WTEC), the massive activity of the EPMA (European Personalized Medicine Association) and the AHA entry for providing annual health recommendation to reach better CVD health results in 2020 (5, 7) (http://www.aaas.org/news/releases/2011/0118convergence.shtml).
Thus our recommendations to encourage the adoption of the SSA approach are:
To strengthen the regulatory international and national rules and their enforcement, enabling the open sharing and discussion, while protecting all partners’ rights and intellectual property.
To protect the documented and recordings of the CHEST meetings as privileged to the participants as well as the shared data bases, technologies and publications.
To involve the ethics professionals, regulatory agencies, and the public at the early stages of the basic research including ongoing periodical updates.
To shorten the review process of research publications.
To adjust the university structure to adopt broad interdisciplinary and responsible education and research.
To simplify and shorten the IP registration processes.
To ensure privacy protection and security of medical records and information distributed via the web, mobile phones, etc., including defining accurate guidelines and strictly enforced regulations.
To develop new sophisticated tools for data analysis and rule discovery for big-data as well as small-data analysis enabling reliable personalized medicine.
Only by joining all forces and providing the right structures and schemes for research and development will we be able to reach the practical goals of the preventive predictive personalized and participatory medicine, promoting better wellbeing to all world citizens.
About the authors
Mira Marcus-Kalish is currently the director for International Research Affairs at Tel Aviv University and a Senior Research Fellow at the Interdisciplinary Center for Technological Analysis and Forecasting. Her main interest areas are mathematical modelling, converging technologies and data mining. Dr. Kalish holds a PhD in Operations Research from the Technion, Haifa, where she has developed a computerized system for ECG diagnosis. Her post doctorate training was at Harvard University, at the Molecular Biology Computer Research and Resource (MBCRR) laboratory, and the Dana Farber Cancer Institute. She was part of the “matrix of biological knowledge” Initiative in Santa Fe and then joined the Weizmann Institute working with Prof. Ephraim Katzir on protein interactions. She worked for IBM Israel before joining Tel Aviv University. Dr. Kalish was and is involved in many EU framework projects, such as: the Nano2Life NoE, SkinTreat, ReNaChip, EpoCan, and recently at the NanoAthero Project and the Human Brain Project flagship.
Hamutal Meiri (a PhD in Neurobiology, the Hebrew University, MBA, Tel Aviv University) was a faculty member in brain development in the medical schools of Tel Aviv University, Technion, and NYU. Then she was the first Director of Israel National Committee of Biotech, served as the Consortium Director of Israel Chief Scientist Magnet program (Biotech), Head of Israel Telemedicine Industry Forum, and the Director of North Carolina-Israel Science and Technology Fund. In 2001 she became the CEO of DTL, an Israeli biotech start-up company that developed predicting and prevention tools of preeclampsia that was acquired by hylabs, Rehovot. She was the Coordinator of EC Health Project Pregenesys (FP6) and from hylabs she initiated EC Health Project ASPRE (FP7) where she is the Exploitation Director. She is also the CEO and Chairman of TeleMarpe involved in Risk Management in NanoAthero (EC FP7).
Acknowledgments
The writing of this manuscript was sponsored by the NanoAthero Project (European Commission FP7 NMP.2012.2-2 Project #309820) to MMK.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors declare no conflict of Interest.
Ethical conduct of research: Not applicable.
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