Santaló and Berdasco Clinical Epigenetics (2022) 14:44 https://doi.org/10.1186/s13148-022-01263-1 REVIEW Open Access Ethical implications of epigenetics in the era of personalized medicine Josep Santaló1 and María Berdasco2,3* Abstract Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatiza- tion as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all popula- tions equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflec- tion on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determin- ism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society. Keywords: Epigenetics, Ethics, Autonomy, Privacy, Responsibility, Social justice, Personalized medicine, Stigmatization Background diagnosed patients and struggle to offer optimal care to Despite the best efforts of healthcare professionals to manage disease. A paradigm shift is required where a treat human diseases such as cancer or chronic dis- specific individual could be identified and managed not in eases, the current public health model of post-diagnos- a community-based environment but under the so-called tic management is unsustainable. Most of clinical units personalized medicine (or precision medicine). Indeed, are already unable to cope with the number of newly the World Health Organization is committed to foster the implementation of personalized medicine in transla- tional research and health systems for better diagnostics *Correspondence: mberdasco@carrerasresearch.org 3 Epigenetic Therapies Group, Experimental and Clinical Hematology and in the follow-up of citizens and patients [1]. The use Program (PHEC), Josep Carreras Leukaemia Research Institute, Badalona, of state-of-the art technology, especially the *omics (i.e., Barcelona, Catalonia, Spain genome-wide genetic information or full transcriptome Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 2 of 14 analysis), has facilitated a better understanding of the models are limiting factors to the implementation of epi- molecular basis for main human disorders. Not only genetic-based biomarkers in neurological disorders. that, but there is an increased knowledge on how envi- Undoubtedly, the flexibility of the epigenome has gen- ronmental factors influence disease development and erated another enticing strand of studies to understand progression, being epigenetic factors at the forefront of how epigenetic changes (associated with disease) can be the molecular links between disease and their influencing linked to lifestyles and environmental exposures, includ- factors. At present, the accumulated molecular knowl- ing diet, physical activity, tobacco smoking, alcohol edge is being transformed towards a strategy for a bet- consumption, exposure to chemical or physical agents ter clinical decision-making and the development of new or psychological stress, among others (Fig. 1) [12]. The therapeutic paradigms. question is: Could epigenetic information be used to Following from this matter, a tremendous progress monitor lifestyle interventions on patients designed to related to the scientific knowledge on epigenetic contri- reduce disease risk or progression? Metabolic diseases bution and its development toward translational research including type-2 diabetes [13] and obesity [14] are at the leading to implementation in the clinic has being devel- forefront of such approaches. Patients suffering from oped in the last years [2]. The reversible nature of epi- type-2 diabetes respond differentially to exercise pro- genetic factors has opened up exciting opportunities to grams, and their responses are associated with promoter revert aberrant epigenomes, and consequently, the field methylation of the PPARGC1A gene which encodes for a of epigenetic-based drug discovery has generated sev- protein involved in the control of glucose and fatty acid eral small- molecule inhibitors that are already in clinical metabolism [13]. practice or under clinical trials (e.g. the DNA methyl- Given the increasing research activity on epigenetic- transferase inhibitors azacytidine or decitabine, or the based biomarkers together with the connection with histone desacetylase inhibitors vorinostat, romidepsin, environmental conditions and lifestyle and its reversible belinostat or panobinostat, among others) [3, 4]. Simi- nature, the field of epigenetics has attracted a great deal larly, multiple epigenetic biomarkers such as those pre- of interest in both the social sciences and humanities. dicting response to lifestyle intervention or disease The discussion of whether epigenetic data pose impor- diagnosis are now on the market. The global epigenetics tant new challenges that can lead to an ethical-legal market size is expected to reach 22.05 billion (USD) by framework very different from that generated by the use 2025, according to a new study by Grand View Research. of other molecular biomarkers (e.g., genetic data) or if it Cancer epigenetics is the spearhead for the poten- just introduces an increased degree of complexity in “old” tial applications of epigenetics in clinical management ethical, social and legal issues (ELSI) is a controversial with epigenetic-based biomarkers successfully proven in but timely debate [15, 16]. However, although solid sci- cancer diagnosis, prediction of tumor progression and entific evidence has yet to be generated to understand prediction of therapeutic response [2]. Epigenetic bio- certain epigenetic processes and their association with markers also possess the potential to be used as screening the disease (especially those related to the influence of tools including tests for colorectal cancer (e.g., detec- environmental factors or transgenerational inheritance, tion of the CpG methylation levels at septin 9 gene [5] or among others), now is the time to anticipate the discus- vimentin [6]) and can act as predictive markers for esti- sion and identify the risks to propose preventive meas- mating the response to chemotherapy (e.g., MGMT pro- ures [17, 18]. moter hypermethylation in glioblastomas [7]). Epigenetic Repeated questions have arisen in forums for ethical abnormalities have been also detected in common neu- discussion in the last years. Some of the concerns are rological diseases, such as amyotrophic lateral sclerosis, not exclusive of epigenetic research and are contained Parkinson’s disease or Alzheimer’s disease as well as vari- in ethical guidelines for biomedical research involving ous psychiatric diseases including schizophrenia, major human subjects such as the Belmont Report [19] and the depressive disorder or posttraumatic stress disorder [8]. Declaration of Helsinki [20]. However, the complexity of Although the number of preclinical studies on the poten- some epigenetic concerns is increased. To mention some tial biomarker use of epigenetic alterations in neurologi- examples: given the possibility of evaluating the conse- cal and neurodegenerative disorders is increasing (e.g., quences of lifestyle habits on health through epigenetic α-synuclein methylation in Parkinson’s disease [9] or biomarkers, where is the limit of individual responsibil- promoter methylation in genes associated with deregula- ity for their own or even the next generation’s health? tion of the amyloid-β (Aβ) peptide in Alzheimer’s disease In a hypothetical case where an available epigenetic test [10, 11]), they are still not implemented into clinical prac- to detect that an increased risk of having lung cancer is tice. Technical limitations and lack of appropriate in vivo a consequence of the smoking habits of the patients, should the health system be designed accordingly to Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 3 of 14 Fig. 1 Epigenetic-based biomarkers to monitor human diseases. The effects of lifestyle, environmental exposures (at individual or transgenerational level) or the genetic background, among others, are well-known influencing factors of the epigenome. In spite of the growing number of proposed biomarkers associated with human diseases, some technical limitations need to be solved including the assessment of causality, the establishment of reference epigenomes or the cell-type specificity. On the ethical, political and social dimension a deep discussion on the role of epigenetics as determinants of health and the impact of public health policies and personalized medicine is required the patient’s responsibility on this action? On the other In this review, we will explore these and others con- hand, nowadays it is widely accepted that specific envi- cerns—mainly associated with autonomy, privacy, ronmental toxins—pollution, plastic components, use of equal opportunities and responsibilities—in epigenetic pesticides or hormones in food—are known (or under research, highlighting the main technological limitations suspicion) to influence disease on-set, at least in part, by and challenges to be answered before advancing from epigenetic mechanisms. According to this, the question theoretical to practical dimension. We end with brief arises: Who is liable of such expositions? Undoubtedly, comments on how misinterpretations of the epigenetic policy decision-makers and public policies must acquire influence on disease could lead to a way of non-genetic an increased responsibility. Assuming that social and/or determinism and a reflection on whether epigenetic political structures of the population could influence the research has the potential to jeopardise personalized risk of epigenetic based diseases—with low socio-eco- medicine interventions at the expense of reinforcing nomic classes at the most “epigenetically disfavored” situ- public policy measures. We have employed a system- ation—these vulnerable populations would be at a higher atic search strategy that utilized the PRISMA Statement risk of social discrimination and inequality in the univer- to conduct the review [21]. We have conducted search- sal access to epigenetic-based medical care. ers on the PubMed and Google Scholar databases for Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 4 of 14 peer-reviewed journal articles published in English. The disease causality has been proven? Causal variants are the keywords used as search terms were: epigenetics, eth- optimal candidates for clinical validation as a first step ics, autonomy, privacy, responsibility, social justice, per- towards biomarker actionability; (iv) clinical value of the sonalized medicine, transgenerational inheritance or biomarker. The magnitude of the disease risk and severity synonyms. as well as the potential to revert epigenetic risk variants through specific treatments should be examined. Communicating epigenetic‑based risk Whereas the “which” and “when” responds to the tech- assessments: which, when and how nical validation of the epigenetic discovery, the “how” As we have a very complex and dynamic epigenome, focuses on the individual. Communicating disease risk/ which depends on the tissue, age, exposure to environ- outcome is a difficult and complex process, but undoubt- mental stimuli, lifestyle or pathological situations, among edly, finding the best way to communicate the informa- others, we do not have a unique epigenome during our tion to the patient encourages a stronger relationship lifetime [2, 22]. Moreover, it is also difficult to generate a between health professionals and their patients, a greater so-called normal epigenome which is comparable to any confidence in health systems, and may globally improve specific situation (Fig. 1). Consequently, the elaboration the quality of health care. Although there is no single of epigenetic maps involves the quantification of multi- formula, there are multiple recommendations aimed to ple situations and the generation of a large volume of obtain optimal communication practices including facili- personal data that is being accumulated in secure data- tating personalized information (e.g., adapted to age and/ bases [23, 24]. International initiatives to unravel the epi- or sociocultural background) by using presentations in genomes at global level have been launched in the last multiple formats, providing honest and objective infor- decades, placing particular attention on the International mation, allowing for sufficient time for listening and Human Epigenome Consortium (IHEC), a global consor- interpretation, attention to the expression of emotions, tium with the primary goal of setting up high-resolution and respecting the sociocultural moral values and deci- reference human epigenome maps for normal and dis- sions of the patients, among other recommendations ease cell types [25]. In light of the growing amount of [27]. Public measures aimed to facilitate the professional epigenomic research data and health records that are training in epigenetic and ethical associated matters will being collected, the IHEC consortium has incorporated improve the communication process (Fig. 2). the Bioethics Working Group to identify and discuss The action of communicating an epigenetic-predic- current and emerging ethical concerns of epigenetics tive result itself could imply a risk of “burdening” some research, and to elaborate guidelines for a better ethical members of society. This could occur when the possi- assessment. bility to revert the risk is presumed to be dependent on Translating complex epigenetic research informa- the individual’s behavior, but the individual has reduced tion for a non-specialized public represents a challenge effective possibilities to alter his/own behavior or envi- for communication strategies (Fig. 2). Which epigenetic ronmental exposures. What may also occur, is that the information should be communicated to the patients? proposed changes to the individual’s behavior are not When can a biomarker be considered in the clinical set- followed due to what may be described as a moral weak- ting? To answer these questions and provide an ethi- ness of the individual, by the proponent practitioner. One cal and legal advice on this matter, the IHEC Bioethics example of this is poor accessibility to sources of healthy Working Group propose to check the following points food or limited possibilities to move from “unfavorable” previous to communicate epigenetic information [26]: environmental exposures to improve the health of vul- (i) data accuracy. Quality control processes are required nerable sociocultural populations. For example, if the epi- (technical validation), and the replicability of the find- genetic test reveals a high risk of suffering type-2 diabetes ings should be demonstrated in a clinically accredited derived from obesity but there are limited possibilities to diagnostic laboratory before any research results are improve food habits, should the test be communicated? returned. The origin/source of the epigenetic data, such Alternatively, if the patient has a long history of breach- as the cellular and tissue composition, the age and gender ing dietary suggestions, is it ethical to communicate to of the individual, needs to be considered; (ii) stability of him/her the epigenetic implications of such behavior? A the epigenetic-based biomarker. Since epigenetic marks similar situation appears in those cases of patients with are dynamic, does the biomarker remain stable overtime? high risk or poor prognosis where there is lack of truly Epigenetic analysis at different time points is highly rec- effective preventive or curative strategies. Should it be ommended; (iii) causality of the epigenetic mark. Is it reported in these cases? In summary, knowledge of the merely a significant statistical association? Is it a statisti- degree of risk or disease outcome can lead to the viola- cally inferred variant? Or are they causal variants where tion of individual rights and promote discriminatory Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 5 of 14 EPIGENETIC ETHICAL, LEGAL AND SOCIAL ISSUES (ELSI) PRIVACY AND PATIENT AUTONOMY RESPONSABILITY CONFIDENCIALITY “Bad” behaviours: feelings of Risk of stigmatization and Retrospective vs prospective guilt, rejection or shame discrimination: reflection of lifestyle and environmental Risk of discrimination: New models of informed misconducting good citizen vs bad citizen consent to include lifestyle and enviromental exposures Risk of re-identification Moral responsability: who will take decisions PDA implementation Unexpected findings Individual vs collective Transgenerational inheritance: responsability on next-generation ACTIONS TO IMPLEMENT EPIGENETICS IN HEALTH SYSTEMS DEFINITION OF A DEVELOPMENT OF COMMUNICATION STRATEGY PUBLIC POLICIES Which and when epigenetic information Establishment of a general regulation on data should be communicated? Biomarker protection technical validation: accuracy, stability, robustness Promotion of healthy habits/enviroments in vulnerable populations How should the information be given? Professional training Promotion of equal access to biomedical research and clinical management Health literacy understand health-related issues Balancing personalized medicine strategies and public health policies Strategies adapted to socioeconomic and cultural conditions Incorporation of professional training in ELSI Avoiding moral judgements and Science dissemination strategies to general discrimination public Fig. 2 Ethical, legal and social issues (ELSI) and challenges associated with the use of epigenetic-based biomarkers in the management of human diseases. Specific ELSI considerations on patient autonomy, personal data privacy and confidentiality and personal responsibility are derived from the intrinsic epigenetic characteristics (upper panel). To tackle these ELSI concerns and to favor the implementation of epigenetic-based approaches in medical care some challenges have been identified. On one side, and given the complexity of epigenetic mechanisms, future communication strategies aimed to ensure the understanding of the epigenetic information during medical decision making are strongly recommended (down, left). On the other hand, public policies such as the definition of general laws on data protection, the promotion of equal access to healthy environments and biomedical services to all citizens or the development of educational scientific programs for public but also healthcare professionals are strongly encouraged (down, right). The engagement of the scientific community and health-care professional with policy-decision makers and general public would definitively lead to new biomedical practices and transformative change in health promotion and medical care Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 6 of 14 reactions. On the other hand, additional concerns such when it is in our hands to make it change can generate as patient autonomy or the ethical responsibilities of the feelings of guilt, rejection or shame. These feelings can healthcare professionals facing non-actionable informa- be increased in those cases where there is responsibility tion should be also considered. The “non-conditioning for the offspring accordingly with the transgenerational information” paradigm followed in conventional “genetic epigenetics concept-defined as the molecular mechanism counselling” should be seemingly respected to preserve by which environmental exposures and lifestyle decisions the autonomy of the subject (see “Patient autonomy” can affect the offspring directly through the gametes or in section). Like communication of genetic counselling, utero exposures during pregnancy [32]. the ethical obligations aimed to promote the duty of dis- In a more practical aspect, the inclusion of lifestyle closure actionable epigenetic risk may also be applica- aspects inferred through epigenetic biomarkers should ble in this case. In summary, there are some risks in the lead to the reconsideration of new models of informed communication of epigenetic results that could be bal- consent. Informed consents for disease risk predictions anced by giving appropriate information from epigenetic should be adapted to accommodate for the patient’s experts. The creation of specialized services guided to age, level of education and engagement. Informed con- provide “epigenetic counselling” and/or the promotion of sent should clearly contain the risks and the benefits, genera public dissemination of science should be consid- the harms associated with the screening, and the exist- ered as a tool to facilitate the transmission of epigenetic ence of alternative prediction methods [33]. The inclu- knowledge to non-epigenetic experts and general public. sion of lifestyle data, its connections with epigenetics and the consequences of this inference can generate excess Ethical implications of epigenetic‑predictive information that hinders understanding and, therefore, biomarkers the patient’s ability to identify the relevant information In sharp contrast with the extensive literature built-up on associated with their clinical decisions and an autono- the ethical implications of genetics, the references to the mous choice. What does an autonomous choice mean? ethical implications of epigenetics research are less docu- It means an intentional and voluntary choice taken after mented although an increasing attention has been paid in an appropriate understanding of the information, and the last years. The same cannot be said for the number importantly, a decision in line with patient’s personal val- of ethical concerns associated with epigenetics given that ues [33]. However, the reality at the clinical environment the consequences on epigenetic research could have an is that there is a saturation of ethical and legal documents impact both at the individual and social level. The revers- (mainly the latter) to which the patient is subjected to ible nature of epigenetic factors—and the potential to [34]. The creation of new informed consent documents revert or prevent aberrant epigenomes—together with adapted to epigenetic research should avoid increasing its link to environmental exposures or personal behav- their complexity and ensure that the basic principles of ior creates a new scenario for debate on environmental informed consent are maintained. In this regard, tiered– justice, social and personal responsibilities on health pro- layered–staged informed consent has been proposed as motion or intergenerational equity, among others [16, an appropriate model for epigenetic-based biomarkers 28]. [35]. The tiered–layered–staged informed consent, which In this section, we will restrict to the main ethical was originally proposed for commercial personal genome issues associated with the development and implemen- testing [36, 37], is based on three components: (1) tiered, tation of epigenetic-based biomarkers for assessment of meaning that individuals have the option to differentially disease risk and/or disease outcome, including (i) patient consent to different parts of the treatment or testing in autonomy; (ii) privacy and confidentiality; (iii) personal function of their ethical, personal or social preferences. responsibility for health; and (iv) justice and equality of For example, individuals could give their consent only to opportunities for health promotion (Fig. 2). perform a predictive test when a clinically actionable tar- get exists [35]; (2) layered, as the informed consent model Patient autonomy incorporates layers of complexity ranging from minimal Epigenetics provides additional information about life- information that could be understood by all individuals style (e.g. diet, obesity, smoking, hormone supplemen- towards additional layers with more detailed informa- tation) [14, 29, 30] and the environment (e.g. exposure tion; and (3) staged, which means that the information to endocrine disruptors) [31] to which the patient has is given in several stages during the clinical process. In been or is exposed. To the extent that the lifestyle could practice, the information is accommodated during all be inferred from the epigenetic state, a change in the steps of the screening test, and the informed consent is principle of autonomy can occur. The knowledge that a renewed accordingly [36]. Although the tiered–layered– “bad” lifestyle inevitably leads us to suffer a pathology staged model improves how information is distributed Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 7 of 14 to the patient, and could strongly contribute to organ- parties, including employers, insurers, family, friends or ize and resolve the complexity and dynamic nature of healthcare providers. An evaluation of the risk is needed the epigenetic information, for some authors it lacks the before implementation of epigenetic-based screenings in support for the processing of the information on func- the population, especially in vulnerable groups (e.g. lower tion of the patient’s value [35]. The implementation of socioeconomic groups or ethnicities, among others) to Patient Decision Aids (PDA), defined as evidence‐based avoid this non-genetic discrimination. tools designed to help patients make specific and delib- Re-identification of the sample donor is a crucial ethi- erated choices corresponding to their health decisions cal issue associated with privacy in genetic research [23, that supplements clinicians’ counselling [38], is strongly 46, 47]. Whether epigenetic information stored in pub- recommended as a mechanism to include the patient’s lic databases also exposures to genetic information is own values [35]. Since epigenetics adds uncertainty to the under strong debate. Specifically, whole-genome bisulfite outcome of the disease screening (due to the potential sequencing (WGBS) to determine genome-wide CpG ability of reversion) as well as generates a personal deci- methylation provides DNA sequence at base-pair reso- sion about whether a change in lifestyle is possible, the lution. While absolute data confidentiality and privacy autonomous decision of an individual for being included cannot be guaranteed regarding high-throughput epig- in disease prediction test acquires an added dimension. enomic data affecting DNA, some measures have been Future strategies aimed to promote the informed consent proposed to mitigate the risk of re-identification [23]. process and the autonomous choice in line with own val- First, removal of indirect genotype information (e.g., ues should be developed by the health-care system and single-nucleotide polymorphisms, SNPs) by pre-filtering policy-makers. prior to open-access release using existing algorithms and genotyping resources or masking sites (CpGs or Health information privacy and confidentiality probes) that have common SNPs is recommended. How- Privacy and confidentiality have been broadly discussed ever, following the guidelines of The Cancer Genome in the literature on the basis of genetic research [39, 40]. Atlas (TCGA) project, somatic genetic mutations could Whether epigenetic research creates a new perspective be reported (but not germline mutations) [23]. By con- or it just maintains the same concerns with a (probable) trast, the intrinsic variability of epigenetic markers increased complexity is under strong debate [15, 41]. As depending on tissues or age, for instance, may act as a far as the epigenetic consequences on the privacy and safeguard towards re-identification efforts. confidentiality of the individual’s health information is The second aspect refers to how concerned are donors concerned, we have, above all, to introduce the defini- and the general public. It is necessary to improve the tions. Privacy refers to the individuals’ right to control communication with the sample donor to facilitate the acquisition, uses or disclosures of their identifiable understanding of the risks and benefits of the analysis. data relative to health; whilst confidentiality defines the Elaboration of standard consent information documents obligations of those who receive health information to and data-access agreements are highly recommended. respect the privacy interests of the data donors [18]. Whether sensitive information concerning lifestyle Epigenetic data present the same privacy and confiden- could be inferred from epigenetic information still needs tiality considerations regarding data security as genetic further studies. In spite that a study reveals that smok- data [42]. These previous legal and ethical issues on data ing and alcohol consumption could be revealed through protection in genetic research offer a guideline to han- DNA methylation data from blood [30, 47], these pheno- dle those concerns; however, epigenetic information typic-epigenetic associations have not yet been replicated adds an extra layer of sensitivity by the potential ability for additional behavioral habits, and most importantly, for containing information about the individual’s previ- whether these hallmarks are persistently maintained ous behavior and environmental exposures that intensify in different tissue samples still needs validation. Most the need for data protection [43]. This information, if not probably, debate in this area is mostly anticipatory and confidentially treated, could promote stigmatization and speculative [15, 48]. The truth is that we are not facing a discrimination of specific collectives [44, 45]. Although novel problem but, rather, a challenge that has long been the empiric evidence is still a promise, we could antici- debated for similar studies involving gene expression pate a scenario where participants could enter in an datasets [49] or epidemiological data [50]. epigenetic- predictive screening to determine whether In addition, a recurrent privacy-related debate exists they have developed epigenetic alterations associated on the fact that genetic risk predictors could also result with environmental exposures or lifestyle (e.g., smok- in unexpected findings [51]. Epigenetics poses additional ing, alcohol or drug abuse) [30]. Participants should have challenges derived from its potential to infer lifestyle. As the option to restrict the access of information to third previously mentioned [30], smoking could be associated Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 8 of 14 with specific promoter methylation. What is more, smok- responsibility. Does the certainty of a bad habit really ing-associated DNA methylation changes (e.g., AHRR or impact our behavior? Supposing that the following situ- F2RL3 genes) have been described to predict risk of lung ation occurs: there is a validated epigenetic biomarker cancer [52, 53]. In addition, AHRR methylation has been in clinical use that is responsible for an increased risk also observed in carotid intima-media thickness and con- of colorectal cancer, and that this biomarker could be sequently in cardiovascular risk [54]. In the hypothetical reverted to the healthy value with a diet intervention case where a risk prediction test for lung cancer based on and, consequently, decrease the cancer risk. Undoubt- AHRR methylation exists, should the incidental finding edly, this epigenetic biomarker will create an excep- of an increased risk cardiovascular disease be commu- tional opportunity for preventive medicine. However, nicated? In other words, does unsolicited findings need whether an individual would adopt a change in the life- to be communicated? There is not any consensus on this style after obtaining a risk- predictive testing for disease aspect; however, recommendations have been proposed is not well determined [55]. Most of the current exam- where the bottom line is to evaluate benefits and harms. ples come from screening tests based on the presence or Additionally, the right of “not to know” of the subject, absence of specific genetic mutations in relevant genes. especially in those cases when no efficient treatment is at A systematic review of metadata obtained from multiple hand (as it is currently the case in many epigenetics bio- controlled trials involving adults that have received per- markers), must be respected. sonalized high-risk estimations based on their genetic Finally, it should be highlighted that data protec- background where risk for disease could be reduced by tion and privacy are also a responsibility of the policy adopting behavioral changes reveals that communicat- decision-makers. It is necessary to update the current ing the high risk estimated does not promote a healthy legislations to adjust the problem frames derived from behavior to reduce the risk [58]. Although there is still no epigenetic research (i.e., privacy and anti-discrimination evidence in epigenetic studies, it should not be expected laws) and to establish general regulation on data pro- to be distinct from other molecular tests (e.g., genetic or tection; equally important is to configure secure open- proteomic-based tests). access metadata services adapted to privacy standards One determinant factor in the adoption of a change but allowing an access for the scientific community inter- in the lifestyle after an epigenetic risk assessment is to ested in epigenetic research (Fig. 2). have competent skills to understand and applied the epi- genetic information for a better health. The ability of an Personal responsibility individual to access and understand health information Two conceptualizations of personal responsibility can be in order to take decisions concerning health care, disease drawn: a backwards-looking notion (or retrospective) and prevention and health promotion (named as health lit- a forward-looking notion (or prospective) [55, 56]. The eracy [59]) strongly varies among populations. A recent retrospective vision arises as an interpretation of a detri- study examined the link between health literacy skills mental effect as a causal consequence of a bad lifestyle or and diabetes risk among non-diabetic adults in the Ger- environmental exposures. In line with this vision, an indi- man population concluding that low health literacy was vidual has the possibility to select those behaviors that associated with behaviors that increase the risk of type-2 promote health and to exclude the harmful ones. If so, diabetes such as smoking, inactive lifestyle and poor die- this individual will be automatically identified as a “good” tary habits [60]. Similar correlations have been found for citizen. On the other hand, a person showing unhealthy low health literacy and another diseases, including men- habits (e.g., alcohol abuse, smoking, drug consumption) tal illness [61], cancer screening [62] or the COVID-19 will be stigmatized as a “bad” citizen, increasing the risk pandemic [63], among others. Education level, socioeco- of feelings of guilt, blame and also discrimination. As nomic status and physical limitations to perform routine later discussed in this review, caution should be exerted activities (e.g. limiting chronic diseases) strongly contrib- at this point because whether epigenetic modifications ute to inadequate or problematic health literacy [64, 65]. are the consequence of voluntary decisions of the indi- The intrinsic complexity of epigenetics could be a bar- vidual and the causality of such epigenetic changes on the rier for the understanding of the information about how pathogenesis is still unclear [57]. The real ability of indi- it contributes to the risk for the disease or whether it viduals or even their chances to avoid harmful exposures could be modified by changing our environmental expo- during their lifetime should be placed in context. sures or lifestyles. Accordingly, those groups with low The prospective vision of responsibility focuses on the or problematic health literacy would manifest problems question of who is supposed to take future actions to mit- to adapt their lifestyle or exposures based on their epi- igate the disadvantageous epigenetic effects. Several con- genetic profiles. Even if we assume that an epigenetic cerns should be considered in this context of prospective biomarker could predict the risk and, most importantly, Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 9 of 14 could be used for monitoring the result of risk- reducing which mainly represents the North American approach intervention, the potential benefits will not be accessible developed around the bioethical principles of Beau- for the whole population because of inequality in health champ and Childress [68], focuses mainly on important literacy. ethical dilemmas that occur in health care, in the field of Once again, it must be mentioned that the presumed biomedical research and in the use of new biotechnolo- abilities to change our epigenome by modifying lifestyle gies in medicine. Environmental Ethics focuses on issues and exposure to toxic environments leads to the discrim- pertaining to the relationship between human activities ination or stigmatization in more vulnerable populations. (including health) and the environment or the social, It is questionable how the individuals could really modify economic and cultural contexts [69]. Epigenetics, as a their lifestyle towards a healthier situation. The develop- molecular explanation between the expression changes ment of public policies aimed to promote healthy habits of our genes and the external and internal environmen- and environments in the citizens with a special atten- tal conditions to which we are exposed, represents a great tion to vulnerable populations will facilitate this change. opportunity for the integration of the two conceptualiza- Policies focused on behavior change (individual lifestyle) tions of Bioethics. and policies that either wish to provide people with the Exposures to the environment and individual habits resources to make better decisions (e.g. empowering do not affect all populations equally, creating a violation them with more knowledge, more economic resources, of the principle of distributive justice in bioethics. Fre- etc.), or modify the relevant social configurations that quently, the most vulnerable populations are precisely orient these choices (e.g. nudging, taxation, ban of cer- those that live in the most unfavorable environmental tain products, etc.) have the potential to introduce conditions and that have fewer economic and cultural healthier lifestyles (Fig. 2). Another variable that should resources to mitigate the adverse effects of the adverse be taken into account is the time needed to effectively agent. To mention an example, the pollution generated revert the epigenetic profile towards healthier situation. by industry is often transported far from the geographic Does it take few months or an entire lifetime? location where it occurs [69]. Therefore, the population Another relevant aspect of this prospective vision of that suffers the adverse effects derived from pollution responsibility is related to the transgenerational epi- does not coincide with the population that generates the genetic inheritance. In this case, the personal behavior pollution. If that local population does not have infra- and habits have an influence on the individual offspring, structure to overcome it (for example, detoxification of transmitted through the epigenetic profiles of the gam- contaminated water), there is a clear injury to the most etes, generations ahead [66]. Who is responsible for this vulnerable populations who suffer an unfair distribution inheritance and for its quality? Would it be possible that of risks to potentially alter their epigenome and worsen next generations might hold us accountable for our “mis- their health. Given the pressing importance of promoting conducting” in topics such as pollutants exposure or life- health care, we envisioned that epigenetic mechanisms style both at individual and collective (social) levels? The should be incorporated into the broader discussions of ethics related to what kind of world are we going to leave the social determinants of health inequalities. to our descendants may also include the epigenetics of the next generations. Current ethical and social challenges raised by epigenetics Does epigenetics provide a bridge Limitations in epigenetic research between biomedical ethics and environmental Based on all the issues discussed above, it is clear that ethics? epigenetic research in the context of disease prediction The inclusion of environmental factors and lifestyle and opens new (or potentiate old) ethical, legal and social their influence on health represent a paradigm shift in concerns. This represents a scenario as a starting point the search for predictive models of disease. Is epigenet- for discussion; however, some of the issues for debate ics providing a scientific basis for the transition from are exploratory because specific barriers in epigenetic individualistic predictive models to collective prediction research still need to be overcome (Fig. 1) before advanc- models? Is the molecular alteration at the individual level ing from theoretical to practical dimension in ethical, the objective of the study or, on the contrary, the environ- legal and social discussion [70, 71]. mental factor that brings together a group of individuals Causality is the Achille’s Heel in epigenetic research. the main target? These questions generated by the field Bibliography is full of preclinical correlated associations of epigenetics reopen an old dichotomy between ethi- between an epigenetic alteration and disease states; how- cal schools of thoughts in the field of health: Biomedical ever, whether this association is critical to determine Ethics and Environmental Ethics [67]. Biomedical Ethics, the causality of the disease is poorly understood in most Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 10 of 14 cases. Does promoter methylation of a tumor suppres- changes showing a causal role in diseases. Furthermore, sor gene influence cell proliferation? Or by contrast is the the establishment of “reference” epigenomes implies to gain of tumorigenic properties a trigger of the promoter gain knowledge on cell-type heterogeneity [79] and on methylation? Definitely, one great challenges in clinical the natural variations associated with developmental epigenetics is to distinguish causal changes, so-called stages, that is to say, to understand the normal dynamism drivers, from changes that appeared by chance but did of epigenomes during human cellular differentiation not contribute to the transformed phenotype themselves, and development [80]. These concerns, and others such so-called passengers. This causality acquires an extra level as developing human models, should be solved before of complexity when associations involved an environ- ascribing moral epigenetic responsibilities as a result of a mental factor or lifestyle habits. Smoking has been widely voluntary lifestyle or environmental exposure. associated with epigenetic alterations and increased risk of respiratory diseases (e.g., chronic obstructive pulmo- Epigenetics: tipping the balance in favor of personalized nary disease or asthma) or neurodevelopmental disorders medicine or public health policies? (e.g., child attention-deficit/hyperactivity disorder) at a As Dupras and Ravitsky note [81], the development of the single generation but also in transgenerational inherit- clinical epigenetics concept, that is to say, the translation ance [72, 73]. However, studies involving different human of the epigenetic knowledge to the clinical management cohorts did not allow for conclusions that a causal associ- [2], has the potential to jeopardise public policy measures ation between smoking, methylation and disease output at the expense of reinforcing the personalized medicine exists [72]. Does additional influencing factor exist? Are interventions. The difference is the point at which the methylation levels influenced also by diet, local pollut- focus of disease prevention is. If external factors such ants or age of the study participants? Are DNA methyla- as socioeconomic, cultural or living environments are tion levels affected in a cell-type manner? considered as determinant for health, epigenetics could To solve part of these questions and address epige- provide a molecular mechanism to reinforce the neces- netic causality in basic research, two main strategies are sity of making “better” external conditions aimed to being developed. At one end, it is necessary to consider create “healthier” epigenetic conditions and to reduce data integration tools [74, 75]. Undoubtedly, epigenetic epigenetic health inequalities. This reasoning is in line research centered on a unique epigenetic modification with the implementation of collective preventive strate- will not provide a comprehensive functional view of gies at the policy level [81]. On the other side of the coin, most biological processes and multiple epigenetic marks the emphasis can be on the internal molecular etiology should be incorporated in the biomedical research to of the disease and the search either in the prediction of elaborate a closer in vivo scenario. Not only that, -omics disease risk or progression (biomarker use) or the devel- integration (i.e., transcriptomics, genomics, epigenom- opment of epidrugs to revert aberrant epigenomes. This ics and proteomics) could contribute to outline the second vision is aligned with the personalized medicine functional role of the epigenetic state. Molecular data approaches. In principle, both visions have the potential integration will depend on the design of appropriate to positively impact in the healthcare promotion of citi- approaches for the standardization, annotation and har- zens; however, how to prioritize one strategy represents a monization of epigenetic data, as well as optimization of conflict because public health resources are limited. computational and machine learning methods [76]. On Nowadays, discussion on the balance between ben- the other side, unravelling the functional implications efits and harms of personalized medicine has generated a of epigenetics in a disease could take advantage of the dichotomy. So far, personalized medicine is based on the epigenetic editing tools (e.g., based on CRISPR-dCAs9 stratification of patients based on their molecular profile technology) [77]. By these tools, it is possible to modify (mainly but not limited to genetics) combined with arti- the epigenetic marks at specific loci for the creation of ficial intelligence, which leads to a more person-centered chromatin contexts [78]. By doing so, epigenetic editing heath care in accordance with the “right treatment for the allows to establish the functional effect of the epigenetic right person at the right time” reasoning. A few examples perturbation using cellular and animal models—beyond of the implementation of epigenetic knowledge in per- inferred clues from computational approaches. sonalized medicine exist [2]. However, it is true that this It is equally important to mention the difficulty to number is still too low for considering a relevant impact establish what a “healthy” epigenome means. There on public health. Are the benefits of epigenetic personal- are epigenetic variations that confers an advantage for ized medicine overpromised? Some detractors argue that a biological adaptation in response to environmental personalized medicine’s effect on public healthcare costs (internal or external) stimuli. Such natural epigenetic are unclear [82]. First, personalized medicine requires a adaptations should not be confounded with epigenetic high investment in -omics technologies that are high-cost Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 11 of 14 consuming. And second, it is unclear whether public Genetic and epigenetic determinism in health health systems would be able to sustain specialized drug A third social trend that can also play a role in future treatments for small groups of people that entails a high health strategies is the widely accepted concept of genetic production expense. The possibility that personalized determinism. Genetic determinism derives from a mis- medicine exacerbate inequality in access to health care is interpretation of the influence of the genetic background also broadly discussed [83]. The equal access to the ben- on our phenotype and thus on our health or even on our efits of epigenetic-based biomedical research and clinical behavior. Although it has been discredited and rebutted, management needs to be guaranteed by adopting appro- the attractiveness of it postulates its apparent rationality priate public policies (Fig. 2). which has been maintained in the collective imagination This discussion turns to whether addressing the under- and has a great influence in the perception that society lying causes of the disease, that is to say, disease preven- has of new health biotechnologies and their acceptance. tion would be preferable than to create new specialized Moreover, genetic determinism can also appear in therapeutic strategies. Where public resources should be health when a non-Mendelian or multigenic genetic con- mobilized? Epigenetics could establish a bridge between dition is diagnosed in an individual. In these cases, diag- personalized medicine—the molecular level of the dis- nosis is translated into a given probability of developing a ease—and the epidemiological context of the disease or disease and epigenetics may play a pivotal role in the final the living conditions. Can epigenetics fill the gap between outcome and evolution of the disease. As we have already the personalized medicine and the personalization of mentioned, epigenetics may be the only way to influence health care? [84]. in this outcome. In spite of that, the perception of most However, due to the lack of robust scientific evidence people is driven by genetic determinism and they tend to on the effects of the environment and lifestyle in the epi- believe in the inevitable that is written in genes. genome and their result in impaired health, most of the Epigenetics has been proposed as the rationale to dodge discussion on public health strategies to reduce the inci- genetic determinism in public opinion and daily life [90] dence of human diseases are not implemented in a prac- but new strategies of modifying epigenetic profiles, either tical context. Current experimental models to unravel by changing lifestyles and environmental conditions or epigenetic causality of complex diseases linked to envi- by developing epidrugs can add an overlay of epigenetic ronmental and lifestyle expositions have been developed, determinism on top of the already existing genetic deter- including the Environmental Enrichment (EE) protocol. minism. To avoid this risk, communicative strategies that EE consist on the optimization of the housing conditions transmit the real potential of epigenetic interventions for murine models by providing physical, cognitive, sen- and their consequences should be developed. sorial and social stimulation [85], and it has been used to ameliorate the adverse epigenetic effects associated Conclusions with various neurological and psychiatric disorders [86]. Current ELSI focused on epigenetic research has places Whether this EE model, which emphasizes the mate- upon the table new—or exacerbated old—concerns about rial, organic and molecular traces of experiences, elevate the necessity of incorporating social concerns in basic and models of political and collective intervention is under translational research. Reformulation of informed con- strong debate [87]. Moreover, the personalized medi- sents adapted to the complex epigenetic content, creating cine strategy is nurtured by the increased acceptance of secure pathways to keep and share epigenetic data, or the two social trends: molecularization and biomedicaliza- equally access to health environments and heath care have tion [81]. The first refers to the inclusion in the molec- been incorporated into the epigenetic language. Some of ular arguments and vocabulary for the understanding the ELSI mentioned before are similar to those associated of the human body [88], while the second reflects how with genetic research, but epigenetics adds a new dimen- our life issues are transformed in biomedical ones with sion to be discussed in the ethics forum. How our social an emphasis on life sciences and technologies [89]. The context (e.g., environmental exposition or lifestyle habits) increased knowledge on the epigenetic basis of disease could impact our health throughout epigenetic mecha- and the possibility to revert aberrant epigenomes support nism has markedly influenced the epigenetic discussion the attention in internal determinants of the disease. In in ELSI and, especially, the potential risk of discrimination this context, it has to be underlined that the potential to and stigmatization of vulnerable populations. In our opin- revert the epigenome (e.g., by changing the lifestyle or by ion, caution should be exerted because robust and causal administrating a pill) could exacerbate the risk of “medi- associations between those environmental factors and calization of life” instead of prevention. epigenetic changes are still pending. In contrast, it is clear that society should anticipate and develop an ethical rea- soning from a multidisciplinary point of view. In addition, Santaló and Berdasco Clinical Epigenetics (2022) 14:44 Page 12 of 14 we strongly considered that a determinant concern in ELSI References 1. Vicente AM, Ballensiefen W, Jönsson JI. How personalised medicine associated with epigenetics is communication. We strongly will transform healthcare by 2030: the ICPerMed vision. J Transl Med. recommend the development of communication strategies 2020;18:180. https://​doi.​org/​10.​1186/​s12967-​020-​02316-w. to promote the individual ability to understand epigenetic 2. 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