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Mini-guts in a dish: Perspectives of adult Cystic Fibrosis (CF) patients and parents of young CF patients on organoid technology

Open ArchivePublished:March 06, 2018DOI:https://doi.org/10.1016/j.jcf.2018.02.004

      Abstract

      Background

      Organoid technology enables the cultivation of human tissues in a dish. Its precision medicine potential could revolutionize the Cystic Fibrosis (CF) field. We provide a first thematic exploration of the patient perspective on organoid technology to set the further research agenda, which is necessary for responsible development of this ethically challenging technology.

      Methods

      23 semi-structured qualitative interviews with 14 Dutch adult CF patients and 12 parents of young CF patients to examine their experiences, opinions, and attitudes regarding organoid technology.

      Results

      Four themes emerged: (1) Respondents express a close as well as a distant relationship to organoids; (2) the open-endedness of organoid technology sparks hopes and concerns, (3) commercial use evokes cautiousness. (4) Respondents mention the importance of sound consent procedures, long-term patient engagement, responsible stewardship, and stringent conditions for commercial use.

      Conclusions

      The precision medicine potential of organoid technology can only be realized if the patient perspective is taken adequately into account.

      Keywords

      1. Introduction

      Organoids are 3D cell structures that can be cultured out of human pluripotent and adult stem or progenitor cells [
      • Lancaster M.A.
      • Knoblich J.A.
      Organogenesis in a dish: modeling development and disease using organoid technologies.
      ]. They closely recapitulate the architecture and function of real-life human tissues and they can be applied in fields ranging from disease modeling to drug development and regenerative medicine [
      • Lancaster M.A.
      • Knoblich J.A.
      Organogenesis in a dish: modeling development and disease using organoid technologies.
      ,
      • Bartfeld S.
      • Clevers H.
      Stem-cell derived organoids and their application for medical research and patient treatment.
      ]. Organoids can be stored in so-called Living Biobanks, which enables widespread use of the technology [
      • Beekman J.M.
      • Wang C.M.
      • Casati S.
      • Tuggle K.L.
      • Gulmans V.A.M.
      • Amaral M.
      • et al.
      Biobanking: towards increased access of biomaterials in cystic fibrosis.
      ,
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ].
      Organoid technology could potentially revolutionize Cystic Fibrosis (CF) research and care as it offers a strikingly accurate and personalized model for disease [
      • Saini A.
      Cystic fibrosis patients benefit from mini guts.
      ,
      • Dekkers J.F.
      • Van Mourik P.
      • Vonk A.M.
      • Kruisselbrink E.
      • Berkers G.
      • de Winter-de Groot K.M.
      • et al.
      Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.
      ,
      • Dekkers J.F.
      • Berkers G.
      • Kruisselbrink E.
      • Vonk A.
      • de Jonge H.R.
      • Janssens H.M.
      • et al.
      Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.
      ,
      • Dekkers J.F.
      • Wiegerinck C.L.
      • de Jonge H.R.
      • Bronsveld I.
      • Janssens H.M.
      • de Winter-de Groot K.M.
      • et al.
      A functional CFTR assay using primary cystic fibrosis intestinal organoids.
      ,
      • Dekkers J.F.
      • van der Ent C.K.
      • Beekman J.M.
      Novel opportunities for CFTR-targeting drug development using organoids.
      ]. The development of novel drugs for patients with CF, particularly for those with rare mutations, is challenging, because small sub-groups make it impossible to conduct classical trials. The intestinal organoids, derived from rectal biopsy material of patients, constitute a novel model for stratified drug development and for the prediction of individualized drug response, as they are genetically and functionally similar to patients [
      • Dekkers J.F.
      • Wiegerinck C.L.
      • de Jonge H.R.
      • Bronsveld I.
      • Janssens H.M.
      • de Winter-de Groot K.M.
      • et al.
      A functional CFTR assay using primary cystic fibrosis intestinal organoids.
      ,
      • Sato T.
      • Clevers H.
      Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications.
      ]. Although organoid technology has been predominantly applied in the research setting, the technology starts to impact the clinical care of patients with CF [
      • Saini A.
      Cystic fibrosis patients benefit from mini guts.
      ]. The technology promises to have a far-reaching impact on the lives of patients with CF, particularly on the lives of those with rare mutations (see supplementary material, attachment 1 for more background) [
      • Saini A.
      Cystic fibrosis patients benefit from mini guts.
      ,
      • Dekkers J.F.
      • Van Mourik P.
      • Vonk A.M.
      • Kruisselbrink E.
      • Berkers G.
      • de Winter-de Groot K.M.
      • et al.
      Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.
      ,
      • Dekkers J.F.
      • Berkers G.
      • Kruisselbrink E.
      • Vonk A.
      • de Jonge H.R.
      • Janssens H.M.
      • et al.
      Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.
      ].
      Now that organoid technology promises to thoroughly change the CF field, what do patients with CF actually think of this revolutionary technology? Earlier we showed that organoid biobanking comes with ethical challenges related among other things to the moral and legal status of organoids, consent, commercialization, return of results and governance [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ]. These challenges are not necessarily new, but form a convergence of existing debates on the ethical aspects of genomics, biobanking, big data, and other stem cell technologies [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ].
      In related fields, such as the derivation and use of induced Pluripotent Stem Cells (iPSCs), ethical debate and empirical research on the attitudes of participants have already led to policy recommendations [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Dasgupta I.
      • Bollinger J.
      • Mathews D.H.
      • Neumann N.
      • Rattani A.
      • Sugarman J.
      • et al.
      Patients' attitudes toward the donation of biological materials for the derivation of induced pluripotent stem cells.
      ,
      • Lomax G.
      • Chandros Hull S.
      • Lowenthal J.
      • Rao M.
      • Isasi R.
      The DISCUSS Project: induced pluripotent stem cell lines from previously collected research biospecimens and informed consent: points to consider.
      ,
      • Lowenthal J.
      • Lipnick S.
      • Rao M.
      • Chandros Hull S.
      Specimen collection for induced pluripotent stem cell research: harmonizing the approach to informed consent.
      ,
      • International Society for Stem Cell Research (ISSCR)
      ,
      • Daley G.Q.
      • Hyun I.
      • Apperley J.F.
      • Barker R.A.
      • Benvenisty N.
      • Bredenoord A.L.
      • et al.
      Setting global standards for stem cell research and clinical translation: the 2016 ISSCR guidelines.
      ]. Although some common ground has been established, such as the need for patient consent, debates on the above mentioned questions are still unsettled. What is more, organoid technology is a novel type of stem cell technology that may give a new twist to ethical debates [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ]. In this paper, we aim to provide a first thematic exploration of the patient perspective on organoid technology in order to set the further research agenda. We aimed to recruit respondents for whom organoid technology could be or could become of relevance, i.e. adult patients with CF and parents of young patients with CF, to examine their experiences, opinions, and attitudes with regard to organoid technology.

      2. Materials and methods

      We performed a qualitative interview study to identify relevant themes with regard to organoid technology as perceived by patients with CF and parents of young patients with CF [
      • Corbin J.M.
      • Strauss A.L.
      Basics of qualitative research: techniques and procedures for developing grounded theory.
      ].

      2.1 Sample

      We aimed to collect a wide range of experiences and viewpoints from Dutch patients for whom organoid technology could be or could become of relevance. When we conducted our qualitative interview study, particularly adult patients with CF and young patients detected in the newborn screening were eligible for participation in organoid research. Therefore, we chose to recruit adult patients with CF and parents of young patients with CF (preferably <5 years of age), that had participated in organoid research or not (see supplementary material, attachment 1 for Background on organoid technology and CF).
      Adult patients with CF and parents of young patients with CF were first approached via repeated calls on the website and on other types of social media of the Dutch Cystic Fibrosis Foundation (NCFS). Since mainly adult patients responded to these calls, we additionally recruited parents of young patients via treating physicians in the Wilhelmina Children's Hospital (WKZ).
      In total, we conducted 23 interviews with 26 respondents: 14 adult patients and 12 parents of young patients with CF (see Table 1, Table 2 for Characteristics of the study population). Since organoid technology was emerging in the CF field, for those respondents that had participated in organoid research the processes around retrieval of rectal biopsy material, consent, the research project, and long-term storage of organoids varied (see Table 1, Table 2, and supplementary material, attachment 1 for Background on organoid technology and CF). The time span between their variable experiences (Table 1, Table 2), including consent, and the interview varied between roughly a couple of months and two years. Due to poor recall of their experiences, we could not calculate exact time spans.
      Table 1Characteristics of adult patients.
      Patients

      (n = 14)
      Participated in organoid research

      (n = 5)
      The participation of adult patients in organoid research was variable in terms of the processes around retrieval of the rectal biopsy material, consent, use, and long-term storage of the gut organoids (see supplementary material for background on organoid technology and CF). 3 patients participated in a specific organoid research project and had given biobank consent. 2 patients could not recall the context of their participation in organoid research.
      Did not participate in organoid research

      (n = 9)
      Gender
       Male37
       Female22
      Age (years)
       18–3012
       30–5023
       >5024
      Education
       Primary, lower secondary general, or lower vocational00
       Higher secondary general or intermediate vocational13
       Higher vocational or university46
      Treating hospital
       University Medical Center, Utrecht15
       Erasmus Medical Center, Rotterdam01
       Haga Hospital, The Hague43
      a The participation of adult patients in organoid research was variable in terms of the processes around retrieval of the rectal biopsy material, consent, use, and long-term storage of the gut organoids (see supplementary material for background on organoid technology and CF). 3 patients participated in a specific organoid research project and had given biobank consent. 2 patients could not recall the context of their participation in organoid research.
      Table 2Characteristics of parents and their children.
      Parents

      (n = 12)
      6 interviews were conducted with either the father or the mother of the child, 3 interviews were conducted with both parents.
      Whose child participated in organoid research

      (n = 10)
      The participation of young patients in organoid research was variable in terms of the processes around retrieval of the rectal biopsy material, consent, use, and long-term storage of the gut organoids (see supplementary material for background on organoid technology and CF). Parents of 6 children had provided biobank consent, of whom 1 child had participated in a specific organoid research project, and 5 children participated in the monitoring program (see supplementary material, attachment 1 for Background). Parents of 2 children could not recall the context of their participation in organoid research.
      Whose child did not participate in organoid research

      (n = 3)
      These 3 parents consisted of the mother and father of one child that had not (yet) participated in organoid research and one mother of 2 children, one of whom did participate and one of whom did not participate in organoid research. Therefore the number of parents does not add up.
      Gender
       Male61
       Female42
      Age (years)
       30–4083
       40–5020
      Education
       Primary, lower secondary general, or lower vocational00
       Higher secondary general or intermediate vocational40
       Higher vocational or university63
      Children

      (n = 10)
      Participated in organoid research

      (n = 8)
      The participation of young patients in organoid research was variable in terms of the processes around retrieval of the rectal biopsy material, consent, use, and long-term storage of the gut organoids (see supplementary material for background on organoid technology and CF). Parents of 6 children had provided biobank consent, of whom 1 child had participated in a specific organoid research project, and 5 children participated in the monitoring program (see supplementary material, attachment 1 for Background). Parents of 2 children could not recall the context of their participation in organoid research.
      Did not participate in organoid research

      (n = 2)
      Age (years)
       2–321
       3–430
       4–510
       >521
      Treating hospital
       Wilhelmina Children's Hospital, Utrecht70
       Sophia Children's Hospital, Rotterdam11
       Radboud Medical Center, Nijmegen01
      a 6 interviews were conducted with either the father or the mother of the child, 3 interviews were conducted with both parents.
      b The participation of young patients in organoid research was variable in terms of the processes around retrieval of the rectal biopsy material, consent, use, and long-term storage of the gut organoids (see supplementary material for background on organoid technology and CF). Parents of 6 children had provided biobank consent, of whom 1 child had participated in a specific organoid research project, and 5 children participated in the monitoring program (see supplementary material, attachment 1 for Background). Parents of 2 children could not recall the context of their participation in organoid research.
      c These 3 parents consisted of the mother and father of one child that had not (yet) participated in organoid research and one mother of 2 children, one of whom did participate and one of whom did not participate in organoid research. Therefore the number of parents does not add up.

      2.2 Data collection

      The interviewer, SNB, conducted the interviews between June 2015 and February 2016. The interviews were held in Dutch, they lasted between 50 and 80 min, and took place at the University Medical Center (UMC) Utrecht or at the respondent's home. SNB used a semi-structured topic list to guide the interviews, which was based on literature, pilot interviews, and comments from the NCFS patients' research advisory board (see supplementary material, attachment 2 for the Interview topic list). The topics evolved following information that was obtained from completed interviews. The REC of the UMC Utrecht assessed that the study was exempt from formal review. Patients and parents provided oral informed consent for their participation.

      2.3 Data analysis

      The interviews were audiotaped, transcribed verbatim, and stored coded. In our data analysis we focused on identifying broad themes. We applied the constant comparative method, which means that data analysis is an iterative process in which we go back and forth to develop codes, concepts, and, lastly more interpretative themes [
      • Corbin J.M.
      • Strauss A.L.
      Basics of qualitative research: techniques and procedures for developing grounded theory.
      ]. SNB coded the full transcripts by labeling units of texts that referred to one or more topics, using NVivo 10 software [
      ]. The codes were developed into higher-order concepts and themes. Reliability was ensured by continuous discussion of the codes and themes during team meetings. Representative quotations were chosen to illustrate the themes and translated into English.

      3. Results

      We identified four interrelated themes concerning different aspects of organoid technology that resonated among all our respondents.

      3.1 Theme one: an ambiguous relationship to organoids

      Most respondents see organoids as both closely and distantly related to them. Only a couple of respondents express a predominantly close or distant relationship. Respondents mention several characteristics of organoid technology that influence their thinking about organoids as closely or distantly related (Table 3).
      Table 3Characteristics of organoid technology that influence the perceived relationship of respondents to organoids in 4 different categories.
      Characteristics contributing to a closer perceived relationship
      The same respondent could mention characteristics of organoid technology that contribute to a closer perceived relationship and characteristics that contribute to a more distant perceived relationship.
      Characteristics contributing to a more distant perceived relationship
      The same respondent could mention characteristics of organoid technology that contribute to a closer perceived relationship and characteristics that contribute to a more distant perceived relationship.
      1. Material nature of organoids
      Organoids relate to the human body

       - Grown out of human material

       - Unique and personal characteristics

      ▪ Same genetic make-up

      ▪ Same biological function

       - Related to bodily integrity

      Living human bodily material

       - Organoids are immortalized

       - Organoids are 3D
      Immortalization enables widespread distribution and use of organoids

      Organoids are just cells

       - Organoids have no feelings or thoughts

       - Intestinal tissue is not sensitive

       - Organoid donors have no physical connection to the organoids

      Organoids constitute a technology

       - created by researchers
      2. Use of organoids
      Use of organoids can impact personal wellbeing

       - Improved treatment through personalized diagnosis and drug testing

       - Use can have negative impact (e.g. a breach of confidentiality)

      Use of organoids can impact personal values

       - Use of organoids can be a positive expression of personal values

       - Sensitive applications, e.g. reproductive cloning, growing whole organs and commercial use can conflict with personal values

      Use while coupled to personal information
      Broad use for research is impersonal

       - Research only impacts future patients

       - Noncontroversial applications do not affect a person's values

      Only others can use organoids

      Anonymous use
      3. Intention for (hypothetical) donation
      Strong motivation for and identification with donation

      Strong ideas about worthy use of organoids
      Weak motivation for donation (e.g. ‘not hindering research’)

      Weak ideas about worthy use
      4. Imagination and language
      The term ‘mini-guts’

      Strong imagination of mini-guts in a dish

      Growing bigger organs or combining organ systems
      The term ‘organoids’

      No imagination of organoids: very abstract

      Merely growing tiny organoids
      a The same respondent could mention characteristics of organoid technology that contribute to a closer perceived relationship and characteristics that contribute to a more distant perceived relationship.
      First, respondents address the two-sidedness of the material nature of organoids. On the one hand, they reason that organoids are immortalized human cells grown out of bodily material that share unique characteristics with the donor. Therefore, most respondents regard organoids as living human materials (quotation 1 in Table 4). Some even regard organoids as living fragments of themselves. On the other hand, immortalization of organoids enables broad distribution and use, which creates a literal distance between patients and organoids. Moreover, respondents argue that organoids are just intestinal cells that have no thoughts or feelings (quotation 2 in Table 4).
      Table 4Quotations from respondents.
      Quotation of respondent
      An ambiguous relationship to organoids1. Parent-6: ‘Yes these are after all living cells and they do something, they have a function. On the screen they show that with the right medication they can grow from small to large, however small that is, so they are alive.
      2. Patient-3: ‘Yes, well, it is so abstract and such a tiny piece of tissue that I don't see anything wrong with it. You spread even more tissue around through blood and urine samples and hair that falls out everywhere.
      3. Patient-11: ‘…so risk free…a part of myself, or a clone of myself that you can experiment on risk free…and from that you hope to get a better quality of life.’
      4. Patient-4: ‘If it is immediately used for research in a more generalized target group and used in large numbers, then yes it seems less personal to me, then it suddenly becomes a very different matter.
      5. Patient-10: ‘In a manner of speaking, yes, mini-gut gives you the idea that you are really talking about an intestine, even if it is only a centimeter in size.
      6. Parent-2: ‘It is in fact a part of him, so it is…everything that it is, is also him, so it is important that a link remains between him and the mini-gut, precisely because they could find something that could benefit him too, but it is not a part of him anymore; the way I see it they are real pieces of (son's name).
      The hopes and concerns related to the open-endedness of organoid technology7. Parent-7: ‘Yes that is actually quite strange, something living outside your body, that's really out there, we're sitting here in Brabant and a piece of (son's name) is sitting in Utrecht or wherever it's being kept, I don't know…if you think about it it's quite strange.
      8. Parent-6: ‘Because for us it is real, I feel that the mini-guts are the future for (name), that everything really depends on whether they can, well, if they can cure, or if we can turn CF into a chronic disease instead of a deadly disease.
      9. Parent-8: ‘Well, in addition to the broader research I expect…that something will come of it for him, that they can do something with it. And preferably he would get a sort of tag for possible follow-up research.’
      10. Patient-4: ‘But maybe the creation of organs or very different purposes that have nothing to do with my disease or other diseases, and so more commercial purposes, then it becomes a more complicated story.
      11. Parent-1: ‘Yes it's just that you want to be kept up to date, we are very aware that you probably get a lot of information that you can't do anything with yourself, but you still want to follow it, you want to stay informed.
      Cautiousness towards commercial use of organoids12. Parent-9: ‘No, not with my child, I think. No, if I think about it, the hospital is fine, but something commercial, no. No, that makes me uncomfortable, I think.’
      13. Parent-4: ‘If I read something like Galapagos…that they are working on CF and they bought a license to use organoids, then I think yes, alright, we're going that much faster.
      14. Patient-2: ‘Think of the pharmaceutical industry profiting from it, and it's also a piece of you. And once they start earning so much money that way, it doesn't feel so great.’
      Dealing with ambiguity15. Parent-8: ‘You have to keep in mind that it will take 10, 15, maybe 20 years before there are any real results. So we are very cautious not to get our hopes up.’
      16. Parent-1: ‘…if they say no then you don't get any research in the area of CF, then probably you will say yes.’
      17. Parent-2: ‘…there must be somebody, a committee or something that can manage it well, good ownership. That I have the feeling that my body parts, or my personal information, are safe there. There has to be a sort of trust in that biobank that it will be handled well.
      18. Parents-6: (mother) ‘Yes but I can also imagine, look, lab technicians keep everything on the basis of the unique number assigned to the organoid, so you would think that it would be quite simple to seal certain information…’ (father) ‘With your DigiD (Dutch government digital identification code)’… (mother) ‘Or with your personal organoid code.’
      19. Patient-7: ‘I would find it logical that there would be some sort of compensation for the use of that material, in terms of pharmaceuticals, in the form of expedited access to drugs or something.
      Second, some respondents mention that the type of application influences their perceived relationship. The use of organoids as a personalized drug testing tool contributes to a sense of closeness. In this case organoids become an extension of the patient's body in the laboratory and testing results influence a patient's well-being (quotation 3 in Table 4). A close relationship is perceived by some if they strongly identify with the use of organoids or if, on the contrary, applications conflict with personal values (see Section 3.2 Theme 2). The use of organoids in an anonymous fashion for noncontroversial broad research purposes, however, feels as impersonal, as some say (quotation 4 in Table 4).
      Third, respondents with strong motives for donation, whether personal or altruistic, mostly express a closer perceived relationship to organoids.
      Fourth, imagination and language play a role in the perceived relationship to organoids. Some respondents vividly imagine organoids as organ-like structures in a dish. This image is strengthened by the term mini-gut that is sometimes used popularly (quotation 5 in Table 4). Others acknowledge that they would perceive a closer relationship to organoids if bigger organ-like structures were created.
      In sum, respondents perceive an ambiguous relation to organoids and they each negotiate the ambiguity of the above-mentioned characteristics in their own way (quotation 6 in Table 4).

      3.2 Theme two: hopes and concerns related to the open-endedness of organoid technology

      The immortalization of organoids and biobank storage combined with a broad consent procedure (see supplementary material, attachments 1, 3 and 4) create certain degrees of open-endedness. All respondents express hopes and concerns related to the open-endedness of organoid technology.

      3.2.1 Hopes related to open-endedness

      Most respondents share the impression that organoid technology could revolutionize CF drug research, which could ultimately lead to personalized treatment. This hope for personalized treatment is their main motivation to donate the organoids to a biobank. Some respondents (would) predominantly donate for the good of future patients, whereas others (would) donate in the hope of benefitting personally. Some respondents, mainly those that had not participated in organoid research or respondents for whom the purposes of future use remain somewhat unclear, have relatively high hopes for personal benefits (quotation 8 in Table 4). Others have more moderate expectations (quotation 9 in Table 4).

      3.2.2 Concerns related to open-endedness

      Concerns mainly revolve around the uncertainty of respondents concerning whether their organoids will be used in their best interests and according to their values. Although a couple of respondents have found some reassurance in the broad consent process (see supplementary material, attachments 1, 3 and 4), most share the following concerns:
      Some respondents mention the possibility that their organoids and related personal information are not being handled respectfully. Moreover, respondents mention that the open-endedness hampers a sense of contribution and identification with the aims for which their organoids are used. Most respondents wish to stay away from unworthy, trivial or unethical applications, such as growing whole organs, reproductive cloning, and purely for-profit use (quotation 10 in Table 4). This would clash with their values. Others explicitly formulate the type of research they wish to contribute to, notably CF research and care. Additionally, some respondents are uncertain as to whether their organoids will be used in ways that could positively impact their future care. Others are actively interested in organoid research and would like to get the opportunity to better comprehend the technology and its meaning for CF (quotation 11 in Table 4). Most parents wish to be able to justify and explain the storage and use of organoids to their child.

      3.3 Theme three: cautiousness towards commercial use of organoids

      Most respondents, including those who have given biobank consent, struggle with commercial use, e.g. by pharmaceutical or biotech companies. Some respondents, including a parent that had consented to biobank storage, even categorically reject the use of organoids by commercial parties (quotation 12 in Table 4). Others accept that we live in a society in which drug development is predominantly market-driven (quotation 13 in Table 4).
      The motives that respondents give for their cautiousness seem to reflect a distrust of commercial parties. First, most respondents fear that commercial parties will not act in the best interest of patients and society. Second, the profit motive is deemed unfair or even unjust (quotation 14 in Table 4). Making money out of severely ill patients is considered to be potentially exploitative and for-profit research may result in exorbitant prices of novel drugs. Third, respondents fear a lack of oversight of the use of organoids. Fourth, some fear negative consequences of commercial use, including the sharing of sensitive information with improper stakeholders (e.g. insurance companies), or perceived unethical applications.

      3.4 Theme four: dealing with ambiguity

      From the previous three themes it follows that respondents have ambiguous attitudes towards organoid technology: (1) they experience a close as well as a distant relationship to organoids, (2) open-endedness of organoid technology strengthens hopes and concerns, and (3) although commercial use is deemed necessary for drug development, it evokes cautiousness. Respondents come up with different ways to deal with their variable values, interests, hopes, and concerns.
      First, respondents acknowledge the importance of initial biobank consent. Respondents that have given broad biobank consent mention a couple of aspects that they experienced to be reassuring. One parent mentions that the information provided in the consent conversation helped to have realistic hopes (quotation 15 in Table 4). Other respondents mention the written information that, for instance, addressed the installment of ethical oversight, the protection of privacy, and the return of clinically useful results (see supplementary material, attachments 3 and 4). Still, most respondents would ideally wish to restrict the scope of initial consent, although most of them had consented or would consent to the broad terms (quotation 16 in Table 4). Some would prefer to donate to CF research exclusively or to limit the sharing of their organoids. Others would like to exclude certain sensitive uses.
      Second, initial consent is generally considered to be insufficient. It should, according to the respondents, be coupled with long-term engagement of participants and responsible stewardship, which includes ethical oversight, privacy protection, transparency, and the fostering of trust (quotation 17 in Table 4). Minimally, respondents share the idea that participants should be informed about major changes in governance or use and about clinically useful results. In addition, most respondents would like access to collective information concerning planned, ongoing, and finalized projects. Some respondents would ideally have access to personal information on the use of their organoids (quotation 18 in Table 4). Some only wish to be asked to re-consent to sensitive applications, whereas others wish to be asked to re-consent to each new research project. Overall, if organoids are used by commercial parties, respondents put forward more stringent conditions for long-term engagement and stewardship, including an emphasis on reciprocity (quotation 19 in Table 4).

      4. Discussion

      This is the as far as we know first study exploring the patient perspective on organoid technology. The four themes that emerge in our qualitative interview study give an impression of the experiences, attitudes, and opinions of Dutch adult patients with CF and parents of young patients with CF with regard to organoid technology. Although our respondents are generally supportive of organoid technology, the first three themes show that they have an ambivalent attitude. Respondents (1) experience a close as well as a distant relationship to organoids, (2) the open-endedness of organoid technology strengthens hopes and concerns: organoid technology is seen as a potential game changer in the treatment of CF; however, respondents express concerns about whether the organoids will be used in their best interests and according to their values; and (3) although commercial use is deemed necessary for drug development, it evokes cautiousness. In the fourth theme respondents come up with several ways to deal with their variable values, interests, hopes, and concerns. They mention the importance of a sound consent procedure, long-term engagement of patients, responsible stewardship, and stringent conditions for commercial use.
      This first exploratory study gives an impression of the relevant themes to set the further research agenda, even though further research is necessary to identify differences among subgroups.

      4.1 Understanding the interests of Dutch adult patients with CF and parents of young patients with CF

      Like iPSCs, organoids should not be seen as a morally neutral alternative to embryonic stem cells [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ,
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ]. Contrary to human embryos, intestinal organoids do not raise questions about intrinsic moral value. Nevertheless, organoids, particularly those derived from adult stem or progenitor cells, are genetically and functionally identical to the donor [
      • Sato T.
      • Clevers H.
      Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications.
      ]. Therefore, donors may have a legitimate interest in managing conditions for derivation, storage, and use [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ]. Our findings inform what the interests of donors, in this case Dutch patients with CF and parents of young patients with CF, might be.
      In the first theme respondents reflect on their relationship to organoids. How can we relate their views to the moral value of organoids [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ]? More specifically, could we regard organoids as sensitive tissue and could they give rise to sensitive applications [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Parker L.
      Using human tissue: when do we need consent?.
      ]? This is relevant, because donors generally have more autonomy-based rights over sensitive tissues and applications and ethical oversight is more stringent [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • International Society for Stem Cell Research (ISSCR)
      ,
      • Parker L.
      Using human tissue: when do we need consent?.
      ]. Respondents do not regard the rectal biopsy material itself as sensitive. Rather, it is the transformation of the biopsy into a 3D immortalized cell line that is genetically and functionally similar to the donor that is considered meaningful, and to some extent as sensitive. What distinguishes organoids from other immortalized cell lines is their 3D structure. Some respondents do find that this feature contributes to their idea of a close relationship to organoids.
      Apart from the creation of organoids itself, organoids can be used in possibly sensitive ways that are partially unforeseen. In iPSC research some types of applications have been marked as potentially sensitive, such as certain basic research procedures (e.g. large-scale genomic sequencing), transplantation into humans, and for-profit use [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Dasgupta I.
      • Bollinger J.
      • Mathews D.H.
      • Neumann N.
      • Rattani A.
      • Sugarman J.
      • et al.
      Patients' attitudes toward the donation of biological materials for the derivation of induced pluripotent stem cells.
      ,
      • Lowenthal J.
      • Lipnick S.
      • Rao M.
      • Chandros Hull S.
      Specimen collection for induced pluripotent stem cell research: harmonizing the approach to informed consent.
      ]. All of these apply to organoid technology and our respondents add to this the creation of bigger organ systems. Despite these and other concerns, respondents are generally supportive of organoid technology, which is in line with other empirical studies on the attitudes of patients towards biobanking and iPSC research [
      • Dasgupta I.
      • Bollinger J.
      • Mathews D.H.
      • Neumann N.
      • Rattani A.
      • Sugarman J.
      • et al.
      Patients' attitudes toward the donation of biological materials for the derivation of induced pluripotent stem cells.
      ,
      • Porteri C.
      • Pasqualetti P.
      • Togni E.
      • Parker M.
      Public's attitudes on participation in a biobank for research: an Italian survey.
      ,
      • Tupasela A.
      • Sihvo S.
      • Snell K.
      • Jallinoja P.
      • Aro A.R.
      • Hemminki E.
      Attitudes towards biomedical use of tissue sample collections, consent and biobanks among Finns.
      ]. For our respondents the hope for personal benefit may have been a somewhat stronger motive to (hypothetically) donate organoids. Patients with CF are not mere donors of bodily materials, they are simultaneously potential end-users of organoid technology. Therefore, their interests could differ from other types of tissue donors. The fear that organoids may not be used in ways that can positively impact their healthcare indicates this personal interest.
      In the third theme, respondents reflect on an area of application that raises specific concerns: commercial use of organoids. Commercial use of human samples is known to be a sensitive topic among patients, donors, and the wider public [
      • Dasgupta I.
      • Bollinger J.
      • Mathews D.H.
      • Neumann N.
      • Rattani A.
      • Sugarman J.
      • et al.
      Patients' attitudes toward the donation of biological materials for the derivation of induced pluripotent stem cells.
      ,
      • Nicol D.
      • Critchley C.
      • McWhirter R.
      • Whitton T.
      Understanding public reactions to commercialization of biobanks and use of biobank resources.
      ,
      • Steinsbekk K.S.
      • Ursin L.O.
      • Skolbekken J.-A.
      • Solberg B.
      We're not in it for the money-lay people's moral intuitions on commercial use of “their” biobank.
      ,
      • Haddow G.
      • Laurie G.
      • Cunningham-Burley S.
      • Hunter K.G.
      Tackling community concerns about commercialisation and genetic research: a modest interdisciplinary proposal.
      ]. Our respondents particularly fear that their organoids might be used for developing CF drugs that will be exorbitantly priced, which may impede access to these novel therapies. This fear is not unfounded given the high prices of the latest generation of CF drugs [
      • Fauber J.
      Kalydeco: a price too high to pay? MedPage Today.
      ].

      4.2 Embedding patient perspectives in practice and policy

      How should the practice and policy of organoid technology be shaped together with CF patients and their parents? In the fourth theme, respondents express that their interests and concerns could best be taken care of through sound initial consent procedures, long-term engagement, responsible stewardship, and stringent conditions for commercial use.
      Donor consent for the collection, storage and use of human samples is generally recognized as an important means of protecting a donor's interests [
      • Council of International Organizations of Medical Science (CIOMS)
      International ethical guidelines for health-related research involving humans.
      ,
      • World Medical Association (WMA)
      WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks.
      ]. Explicit donor consent for the derivation and use of iPSCs is deemed indispensable and we propose extending this prerequisite to organoids [
      • Bredenoord A.L.
      • Clevers H.
      • Knoblich J.A.
      Human tissues in a dish: the research and ethical implications of organoid technology.
      ,
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ,
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Dasgupta I.
      • Bollinger J.
      • Mathews D.H.
      • Neumann N.
      • Rattani A.
      • Sugarman J.
      • et al.
      Patients' attitudes toward the donation of biological materials for the derivation of induced pluripotent stem cells.
      ,
      • Lowenthal J.
      • Lipnick S.
      • Rao M.
      • Chandros Hull S.
      Specimen collection for induced pluripotent stem cell research: harmonizing the approach to informed consent.
      ,
      • International Society for Stem Cell Research (ISSCR)
      ]. Furthermore, several of our findings contribute to the idea that the initial consent procedure has its limitations. Initial consent was deemed insufficient by most of our respondents to manage their hopes and concerns, a perspective that is reflected in other work on the storage and use of human samples [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Lowenthal J.
      • Lipnick S.
      • Rao M.
      • Chandros Hull S.
      Specimen collection for induced pluripotent stem cell research: harmonizing the approach to informed consent.
      ,
      • Hoeyer K.L.
      Donors perceptions of consent to and feedback from biobank research: time to acknowledge diversity?.
      ]. Besides, many respondents had flawed recall of the consent procedure, a well-known phenomenon in biomedical research in general and stem cell research in particular [
      • McCaughey T.
      • Chen C.Y.
      • De Smit E.
      • Rees G.
      • Fenwick E.
      • Kearns L.S.
      • et al.
      Participant understanding and recall of informed consent for induced pluripotent stem cell biobanking.
      ].
      Therefore, we contend that initial consent should be coupled with long-term engagement of participants and responsible stewardship. For iPSC research it has already been argued that donors should be re-contacted to solicit re-consent for innovative, potentially sensitive applications, for the return of individual results, and to seek re-consent from pediatric participants once they reach an adult age [
      • Aalto-Setälä K.
      • Conklin B.R.
      • Lo B.
      Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.
      ,
      • Lowenthal J.
      • Lipnick S.
      • Rao M.
      • Chandros Hull S.
      Specimen collection for induced pluripotent stem cell research: harmonizing the approach to informed consent.
      ,
      • Giesbertz N.A.A.
      • Bredenoord A.L.
      • van Delden J.J.M.
      When children become adults: should biobanks re-contact?.
      ]. We would like to add that at minimum participants should be informed about relevant collective information and major changes in governance [
      • Boers S.N.
      • van Delden J.J.M.
      • Bredenoord A.L.
      Broad consent is consent for governance.
      ]. Participatory medicine initiatives around the globe, however, show that patients can be involved more actively [
      • Prainsack B.
      • Shilton K.
      • Estrin D.
      • Burke J.
      • Hansen M.
      The powers of participatory medicine.
      ,
      • Boeckhout M.
      • Reuzel R.
      • Zielhuis G.
      The donor as partner. How to involve patients and the public in the governance of biobanks and registries.
      ]. The incremental levels of involvement range from informing patients, to consultation, an advisory role, partnership, and ultimately a project in which patients have a leading role [
      • Boeckhout M.
      • Reuzel R.
      • Zielhuis G.
      The donor as partner. How to involve patients and the public in the governance of biobanks and registries.
      ,
      • Noordhoek J.
      • Gulmans V.
      • van der Ent C.K.
      • Beekman J.M.
      Intestinal organoids and personalized medicine in cystic fibrosis.
      ]. The desirable level of involvement is case and context dependent. A higher level of involvement may be necessary if a disease-specific biobank is set up in which participants are both donors and potential end-users, such as the CF organoid biobank, or if organoids are used for sensitive aims. The CF field in the Netherlands already sets the stage for close collaboration among patient organizations, researchers, and physicians [
      • Noordhoek J.
      • Gulmans V.
      • van der Ent C.K.
      • Beekman J.M.
      Intestinal organoids and personalized medicine in cystic fibrosis.
      ].
      Furthermore, public-private partnerships are needed to translate the scientific fruits of organoid technology to marketable drugs for patients with CF, as is acknowledged by our respondents. In general, for the commercial use of organoids to be ethically responsible and widely supported by patients and the public, models are needed that balance potential merits with concerns [
      • Boers S.N.
      • van Delden J.J.M.
      • Clevers H.
      • Bredenoord A.L.
      Organoid biobanking: identifying the ethics.
      ]. In these models, reciprocity is key [
      • Gottweis H.
      • Gaskell G.
      • Starkbaum J.
      Connecting the public with biobank research: reciprocity matters.
      ]. For the field of CF, the ultimate goal of applying organoid technology is the realization of precision medicine. To reach this goal, pro-active negotiation of pricing is prerequisite, particularly in light of recent difficulties with reimbursement of lumacaftor/ivacaftor, a promising CF drug, in the Netherlands [].

      4.3 Limitations

      First, whereas the heterogeneity of our sample allowed us to collect a wide range of viewpoints it also has limitations, particularly because the sub-groups are represented by small numbers. We, for instance, interviewed more adult male patients with CF than female patients, the experience of our respondents with organoid research was variable, and most of the parents we interviewed had a young child that had participated in organoid research. Parents without experience in organoid research were underrepresented. In this first qualitative study, however, it was not our aim to provide in-depth insight into differences among sub-groups, nor to generalize the views of our respondents to the entire population of patients with CF.
      Second, due to low response rates to the open calls, we additionally recruited parents via treating physicians in the WKZ, where most children are exposed to organoid technology. The WKZ professionals have a positive overall attitude towards organoid technology, which may have influenced parents. Nevertheless, parents voiced concerns equally.
      Third, it is likely that patients and parents interested in new developments in the CF field responded most readily to the open advertisements. This could influence their level of knowledge and their desire for pro-active involvement in organoid technology. The educational level of our respondents was above average and consequently they may well have been more informed and articulate.
      Fourth, the timing and process of interviewing may have influenced the views of respondents. Although most respondents were primarily positive regarding organoid technology at the beginning of the interview, they gradually started to voice concerns. Those that had participated in organoid research admitted that for them it was their first opportunity to thoroughly reflect on certain sensitive topics. It remains a question whether these concerns will fade away over time.
      Fifth, patients with CF constitute a distinct group. They have a direct health interest in organoid technology and they are known for their pro-active attitude in their care and in research [
      • Lowton K.
      Trials and tribulations: understanding motivations for clinical research participation amongst adults with cystic fibrosis.
      ].
      The limitations of our explorative study clearly show the need for further future research. In order to analyze differences among sub-groups of patients with CF and to generalize findings to the entire population further empirical research is needed in which qualitative and quantitative approaches are combined and more diverse groups (in terms of e.g. educational level, disease severity, ethnicity, nationality) are included. Moreover, further empirical research should shed light on the perspective of other types of donors and organoids.

      5. Concluding remarks

      Sound governance of organoid technology in CF research and care requires considerations of consent, long-term engagement of adult patients and parents of young patients, responsible stewardship, and responsible models for commercial use. Organoid technology holds a promise for personalized therapy in CF; however, this can only be realized if the perspective of the person in question, i.e. the patient, is taken adequately into account.

      Acknowledgements

      We are grateful to the 26 Dutch parents and patients willing to participate and share their personal thoughts and opinions with our research team. We also acknowledge the useful discussions with Sabine Michel, Margot Geerdink, both research nurses at the Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands, and with Dr. Jeffrey Beekman, Associate Professor at the Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands. We acknowledge Hubrecht Organoid Technology (HUB), The Netherlands, and particularly Robert Vries, Tulay Bayram, and Petra van der Groep, for providing us with a representative version of the patient information letters and informed consent forms for organoid biobank storage (see supplementary material, attachments 3 and 4).

      Funding

      We gratefully acknowledge financial support by the associate professor's stimulation grant, a personal grant awarded to Prof. Dr. A.L. Bredenoord by the UMC Utrecht, The Netherlands.

      Conflict of interest

      The authors declare no conflict of interest.

      Author contributions

      SNB, JJMD, ALB, VG, and JN participated in the design of the study. SNB conducted the interviews, and coded the full transcripts. ALB read and adjusted the full coded transcripts. Adjustment of codes was done by comparison across transcripts and by discussion among SNB, ALB, and JJMD. After they reached consensus, SNB, ALB, and JJMD developed the codes into higher-order concepts and themes that were discussed together with KWB, CKE, VG, and JN. SNB drafted the first manuscript. SNB, KWG, VG, JN, CKE, JJMD, and ALB made substantial contribution to the manuscript and revised it critically. All authors have read and approved the final manuscript.

      Appendix A. Supplementary data

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