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“Medicine for the 21st century must broaden its understanding and appreciation of health and disease while extending its practices to embrace the dynamics of complex adaptive systems integral to much of the disease processes and for patients’ adaptive responses to their disease and its management [1]”. This statement by Joachim Sturmberg captures much of the impetus and goals of this volume, and yet at the same time raises several fundamental ethical issues. What is the basis of this obligation (“must”) to broaden the understanding and appreciation of health and disease? Who will inform medicine as to this new understanding and how will this informing group be chosen? How much and what kind of input will patients have regarding the assessment of their adaptive responses to their diseases and disease management? These are some of the questions that arise from this move towards Systems and Complexity Sciences in Healthcare, and, hence, they are the focus of this chapter, which attempts to clarify and elucidate these questions as well as propose directions for how best to address these coming challenges.

One often used scheme for describing the goals of this movement towards Systems and Complexity Sciences in Healthcare is called P4 medicine [2]. The P4 refers to the four fundamental improvements that this type of medical advance is purported to bring. Medicine will become more predictive, preventive, participatory, and personal. These four goals are fairly straightforward with regard to the terms that are used to describe the goals. By collecting, analysing and integrating large amounts of healthcare data from around the world, healthcare professionals will be able to: (1) become more focused on the individual person, including that individual’s unique health situation (genetics, epigenetics, family history, environment, lifestyle, diet, etc.), (2) predict each individual’s healthcare risks and, hence, (3) be better able to prevent the onset of illness and disease through (4) the increased participation of that individual in making lifestyle changes that will significantly reduce the risk of disease, as well as its duration and intensity. However, though the goals may appear fairly straightforward, there are imposing challenges to accomplishing these goals as many of the proponents of this new approach to healthcare acknowledge.

The challenge in bringing P4 medicine to patients and consumers is twofold: first, inventing the strategies and technologies that will enable P4 medicine and second, dealing with the impact of P4 medicine on society - including key ethical, social, legal, regulatory, and economic issues. Managing the societal problems will pose the most significant challenges. Strategic partnerships of a variety of types will be necessary to bring P4 medicine to patients [2].

The fundamental ethical issues raised by Systems and Complexity Sciences in Healthcare, stated above, fall squarely into this area of most significant societal challenges identified by these P4 medicine proponents. How then to begin to more precisely delineate and address these challenges?

In September 2007, the U.S. Department of Health and Human Services (DHHS), under the direction of Secretary Michael Levitt, announced a major public policy shift in the direction of P4 medicine by rolling out its new program: “Personalized Health Care: Opportunities, Pathways, Resources [3]”. This program was to use the latest developments in genomics, health information technology, and clinical evidence/delivery to provide, “The right treatment for the right person at the right time [3, p. 12]”.

Why unquestionably a laudable goal for the program, one could rightly and readily ask the question, “but had not all patients come to healthcare professionals before this new program expecting that what they received would be the right treatment for them at that particular time?” If so, then why the fanfare regarding the delivery of what had always been a patient’s expectation? The answer to that question was presented at the very beginning of this report, in Secretary Levitt’s Forward, wherein he states that while healthcare has not been very good at delivering this standard of care up to that point in time the promise of Personalized Healthcare is that we can now achieve it [3, p. 1]. Secretary Levitt gave a clear example of why healthcare had failed in the past to deliver the precise care patients expect in the Forward to the second report released by DHHS in November, 2008, “Personalized Health Care: Pioneers, Partnerships, Progress.”

It remains common medical practice to follow a trial-and-error process for finding the right diagnosis, the right treatment and the right pharmaceutical dosage for each patient. Even our definitions of diseases remain rooted in 18th and 19th century terms. We refer to asthma, but there are many varieties of asthma. From a treatment perspective, they are actually different diseases, yet we are barely at the cusp of being able to identify them accurately and provide the right treatment at the first encounter. We refer to colon cancer, but this term is really a surrogate for five different known diseases. We refer to breast cancer, but in reality there is no such single disease - rather, cancers of different kinds may arise in breast tissue. From a treatment perspective, the notion of treating “breast cancer,” as opposed to a cancer that arises from dysfunction in a particular gene-based mechanism, is already outdated. One result is that most women who are treated with dangerous, painful and expensive chemotherapies are receiving treatments that are actually ineffective for their condition [4, p. 9].

The conclusion, reached in both of these reports, is that in too many instances what healthcare is delivering is not in line with patients’ expectations regarding either precision or efficacy. Patients are not receiving the right treatment at the right time, and much of this situation is due to a mismatch between the desires for what patients want healthcare to deliver, and what healthcare actually does deliver. While it is the hope and goal of Personalized Healthcare, by embracing complexity and systems medicine, to improve dramatically upon this problematic situation, one must also acknowledge that the early results of this new approach may well be to make it more evident just how far healthcare is from delivering the right treatment for the right person at the right time. Hence, the first crucial step to addressing the societal challenges of healthcare in the twenty-first century will be to communicate more clearly and comprehensively just how much recent research is indicating we do not yet understand about the complexities of health and disease, and how far we are from delivering timely, effective treatments for each and every patient.

One major obstacle to communicating clearly the actual state of global healthcare is the difficulty in integrating the apparently amazing biomedical advances that are reported almost daily in the mass media into the larger healthcare reality of too many patients receiving ineffective and even harmful treatments. Part of this difficulty resides in the fact that some of these amazing research results are actually challenging and changing traditional concepts of health and disease, as was stated in the 2008 DHHS report. One recent discovery provides a good example of how surprising, and challenging, new findings can be to our traditional concepts of health and disease.

For over 20 years a group of people from Ecuador, who were all related and who all suffered from a metabolic disorder called Laron Syndrome that significantly stunted their growth (most are less that 4′6″ tall), were carefully studied by researchers both to find the cause of their condition and a possible treatment. In 2011, the researchers published their findings which did uncover the genetic basis for their shared condition, along with some remarkable additional features of their “disease” which revealed how apparently simple genetic differences can result in extremely complex and confounding balances between health and disease in human beings. What the researchers discovered was that the same genetic change in the growth hormone receptor (GHR) gene (primarily a single DNA base change from an adenosine to a guanine) resulted not only in the clinically identified deleterious phenotypic differences among this group (e.g. short stature), but also an amazing reduction in the risk of acquiring either cancer or type 2 diabetes [5]. In fact, among the members of the group studied none exhibited type 2 diabetes or malignant tumours while the control group to whom they were compared showed a 5 % rate of type 2 diabetes and a 17 % rate for cancer. Considering the fact that both cancer and type 2 diabetes are recognized as two of the most significant diseases we face globally in the twenty-first century, one could easily ask the question as to which group in the study should have been identified as the “healthy” control group and which the “diseased” group being studied? This question about the health status of the people with Laron Syndrome is made all the more challenging when one notes that approximately one third of the deaths in this group are due to social/behavioural causes (accidents and alcohol) that are likely exacerbated by their difficulties fitting in with “normal” human society (Fig. 14.1). In a society geared towards their physiology, one could reasonably speculate that their average lifespan might in fact exceed that of their “healthy, normal” neighbors.

Fig. 14.1
figure 1

“Normal”—who shall decide?

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Obviously such a finding stimulated additional inquiry and research, which led the authors of a later review article to conclude, “Numerous studies suggest that GH deficiency early in life is beneficial for healthy ageing with likely mechanisms including reduction in cancer incidence and improved stress resistance ….” Yet at the same time, “GH is essential for growth, reproductive fitness, and providing optimal tissue function through life, but at the cost of increased neoplastic disease later in life. [6, p. 308]” This insight into the role of the GHR gene in human biology reveals a balance between health and disease that is built into the very genetic fabric of our human nature. This intrinsic balance will become an ever increasing challenge for healthcare as research uncovers more and more of the intricate biological complexity behind our experience of health and illness. Not only we will be challenged by such genetic complexity, but we will have to address the magnified complexity that will come from combining such complex genetic information with information regarding how our genetic make-up interacts with our environment, our diet, and our lifestyles.

All this complexity will be found in each and every individual patient, as we all have our own genetic and behavioural balances that shape our health and our disease risk. How then will healthcare institutions grounded in complex and systems biology balance the diverse, and potentially conflicting, healthcare needs of entire communities and populations?

For example, over the past several decades clinical experience has shown that if healthcare professionals take a group of patients who have all been diagnosed with the same disease, and treat them all with the same medication, the group will experience four different types of health outcomes: (1) some will benefit in the way that was intended by the healthcare professional treating them, and also have no significant undesired side effects; (2) some will benefit, but also experience significant harmful side effects; (3) some will not benefit, but will experience significant harms; and (4) some will not experience any real benefit or harm from the treatment [7]. The goal of Personalized Healthcare is, of course, to move all of these patients into the group where all benefit and experience no harmful side effects. This goal is to be accomplished by identifying the factors that cause certain individuals to sort to one group or another (these factors could be genetic, epigenetic, environmental, lifestyle, etc., or a combination of some or all of these). Then, drugs or other treatments can be selected that will be tailored to the specific factors of each patient to maximize the desired benefits and minimize the harms (Fig. 14.2).

Fig. 14.2
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The challenges for P4 medicine

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Many ethical issues arise at this point, including concerns regarding the development and availability of all these precision drugs and treatments for all the different types of patients we will discover there are. How will all these precision treatments be developed, and how will they be made available/affordable to the relatively small groups of individuals who might need each precisely tailored treatment? Also, what if the best treatment is to effect a lifestyle change the patient is not eager, or even willing, to undertake? While these issues are indeed formidable, they are also part of our past and current healthcare terrain, and are being taken into account in the extensive discussions surrounding Personalized Healthcare. The hope is that each will be effectively addressed with a combination of advancing technology and prudent healthcare policy.

But what are we to do about the issues that will come as a surprise as a result of our complexity and systems biology research—such as the people in Ecuador with Laron Syndrome? How, and who, decides if it is better to be of abnormally short stature and experience the harms of growth hormone deficiencies in order to avoid the scourges of cancer and type 2 diabetes, or to be more like the vast majority of people who have “normal” levels of growth hormone activity and more average risks of cancer and type 2 diabetes? In response, one can always argue that ultimately research and technology will find a way around dilemmas such as these, but that response does not address the reality of this issue today or guarantee any solutions in the near, or even distant, future. Hence, do we treat children with Laron Syndrome to make them more like us; do we treat all other children to inhibit their growth hormone pathways to address the increasing health problems of cancer and type 2 diabetes, or do we just leave it to individuals to sort out what disease risks they want to run and which they wish to reduce or avoid? Is this last option really healthcare? Is it really the goal of Personalized Healthcare, employing the techniques and technology of complexity and systems biology, just to create more and more options for patients to choose from with regard to what diseases they are willing to risk getting and which they wish to try to avoid? If the goal is to maximize everyone’s health, how will that health be defined and delineated, and by whom? One might respond to this line of questioning by arguing that the Laron Syndrome case is an extreme one, and that it is not representative of the healthcare challenges the vast majority of people will face. Such a response misses the point of this chapter. Though indeed an extreme example, the Laron Syndrome case does reveal the tensions that can arise when healthcare decisions regarding different physiological states are mixed in with strong personal or cultural values or goals. This tension is already a part of our healthcare landscape in the discussion and debates around a variety of conditions which involve genetic differences that result in significant phenotypic differences, e.g. the issue of deafness and the Deaf community.

While many people may identify deafness as a disease, to be avoided, treated, and/or cured, this physiological condition has been recognized by the United Nations as the defining feature of a culture that deserves protection and support [8]. In addition, some members of the Deaf community argue that attempts to treat and cure this condition, such as cochlear implants, are akin to genocide as they seek to end the existence of the community itself [9]. While the justifications and ramifications of this claim continue to generate debate and discussion [9], the underlying tension of defining such physiological differences as diseases or instances of human diversity is much more broadly applicable. Add to that tension the increasing biological evidence that every human being is a genomic mix of both “good” and “bad” traits, and one can begin to see how cases such as Laron Syndrome, where the balance of good and bad traits is relatively dramatic, help reveal the challenges ahead as we attempt to integrate the complexities of systems biology into our healthcare decision-making processes.

How, then, will the goals of Systems and Complexity Sciences in Healthcare be defined, and by whom? If this new approach to medicine is to truly benefit everyone, then does it not make sense that everyone needs to have the opportunity to contribute to the delineation and definition of this new understanding of health and disease, especially since everyone has some genetic features that are considered to be health risks? How else will those working to bring about this change of direction in healthcare know which way to go with all the new and surprising information that will be generated by the research supporting this new understanding?

This need for broad public engagement (not merely public education) in order to develop successfully this new approach to healthcare has already been recognized by individual scholars, community groups, and national committees. Again in the U.S. DHHS, the Secretary’s Advisory Committee for Genetics, Health and Society (SACGHS) identified this need for public engagement in several of its recommendations in its March 2007 report: “Policy Issues Associated with Undertaking a New Large U.S. Population Cohort Study of Genes, Environment, and Disease [10]”.

In chapter Three of this report, “Policy Issues Associated with a New Large Population Study of Genes, Environment, and Common Diseases”, the Committee articulated “a single overarching policy recommendation” that should guide the actions of the DHHS Secretary in implementing the broad population studies that will be a key part of the new approach to healthcare:

As part of the process for determining whether to undertake such a large-scale research project, the HHS Secretary should initiate a thorough consideration of the full range of policy issues outlined in this report. The HHS Secretary should consult and engage the full range of potential partners for such a project during this decisionmaking process, including the public at large, the full scientific community, a wide spectrum of Government agencies and policymakers, and the private sector [10, p. 23].

What the Committee was emphasizing with this overarching recommendation was the recognition that none of the other many recommendations in the report would be useful or successful if this broad public engagement were not undertaken, for both public guidance and public commitment would be necessary for this new approach to healthcare to achieve its purported goods and goals.

This insight into the need for extensive public engagement has been spreading across the genomic medicine landscape. On the website of the National Human Genome Research Institute at the National Institutes of Health there are statements recognizing the necessity of both public participation and public engagement in clinical research if healthcare is to advance in good clinical decision-making and good research methodology, as well as in the development of new technologies [11].

Proponents of Systems and Complexity Sciences in Healthcare will do well to join this movement to integrate public engagement into the development of this new approach to medicine. The questions and concerns raised at the beginning of, and throughout, this chapter can only be addressed well if the public is thoroughly engaged in all aspects of the development and expansion of Systems and Complexity Healthcare. Answers to the issues of who is healthy and what is health are as dependent on social and cultural values and goods as they are on biology and technology. Decisions determining how new technologies and treatments will be applied, and to whom, will require a strong sense of public understanding and goals in addition to the traditional requirement of well-informed consents, because the healthcare of the twenty-first century will contextualize individual patient decisions within the larger healthcare needs and goals of society—as is already the case in the public health arena with regard to issues such as limiting public smoking and the development of public programs encouraging healthier behaviours.

If Systems and Complexity Sciences in Healthcare does indeed bring more surprises and challenges such as the case of Laron Syndrome, then an engaged and invested public will be both the best defence against abuse of any new knowledge or technology, and the best insurance of broad participation in programs that will help everyone move towards the right treatments at the right time. Though such an extensive public engagement will itself be challenging, one might justifiably presume that proponents of Systems and Complexity Sciences should not be daunted by the complexities of a system of broad and continual public involvement in the development of healthcare that truly brings healing and care to each and all.