Donor perspectives on informed consent and use of biospecimens for brain organoid research

Abstract

Debates about the ethics of human brain organoids have proceeded without the input of individuals whose brains are being modeled. Interviews with donors of biospecimens for brain organoid research revealed overall enthusiasm for brain organoids as a tool for biomedical discovery, alongside a desire for ongoing engagement with research teams to learn the results of the research, to allow transfer of decision-making authority over time, and to ensure ethical boundaries are not crossed. Future work is needed to determine the most feasible and resource-efficient way to longitudinally engage donors participating in brain organoid research.

In this article, MacDuffie and colleagues present the first data collected on attitudes of biospecimen donors toward brain organoid research. Donors expressed overall enthusiasm for brain organoid research, alongside a desire for ongoing engagement with research teams to learn the results of the research, to allow transfer of decision-making authority over time, and to ensure ethical boundaries are not crossed.

Main text

Human brain organoids—multicellular, three-dimensional neural tissue structures derived from donated cells—hold great promise for modeling developmental and disease processes in vitro and accelerating the discovery of novel therapeutics (Lancaster et al., 2013). The human brain is particularly challenging to model given its complexity, and efforts to synthesize tissue that mimics neural function raise unique ethical concerns given the brain’s central role in conscious experience and personal identity.

Some ethics scholars express concern that brain organoids will someday evidence more complex abilities (e.g., sentience) that could confer moral status beyond what is typically afforded to in vitro models (Greely, 2021; de Jongh et al., 2022). For now, such questions remain hypothetical (Hyun et al., 2020). Two separate policy reviews published by the National Academy and ISSCR concluded that research with brain organoids should proceed under existing oversight processes and does not (yet) require special review (National Academies of Sciences, Engineering, and Medicine, 2021; International Society for Stem Cell Research, 2021). As the National Academy’s report states: “Notably at no point under current law will the researcher have to consider the characteristics, treatment, or condition of the organoids … The oversight of organoids addresses only the ethical concerns regarding the human donors of the cells from which they are developed” (2021; p. 81, emphasis added).

With this focus on human donors, the primary ethical issue is how to obtain informed consent for the donation of cells used for brain organoid research (somatic or embryonic cells can be cultured into organoids, but here we will focus only on somatic cell donation). The standard approach is to ask donors for broad consent—i.e., consent to use their cells for a range of future research that is unspecified (de Jongh et al., 2022; International Society for Stem Cell Research, 2021). While broad consent complies with current regulatory standards, the acceptability of such an approach when future research includes the generation of brain organoids has been questioned by some scholars (Greely, 2021; de Jongh et al., 2022; Hyun et al., 2020) and has not been evaluated directly with donors.

The goal of this investigation is to understand attitudes of biospecimen donors (or their decisional surrogates) toward initial consent and future use of donor-derived brain organoids in research. Unlike prior interview studies focused on potential donors (Bollinger et al., 2021; Haselager et al., 2020), we chose to interview those in the unique position to provide real-time input on use of their donated samples for brain organoid research. We conducted interviews with 67 individuals: 11 adult donors and 56 parents of child donors (see Table 1; additional details in the supplemental information). Interviews were conducted between July 2021 and April 2022 by the first author (K.M.), a licensed clinical psychologist and experienced qualitative interviewer, and followed a semi-structured interview guide. The guide was developed by the research team with input from collaborators working in brain organoid research. Interviews took place by phone and were audio recorded for later transcription. Due to the lack of public familiarity with brain organoid research (only 5/63 participants recalled hearing the phrase “brain organoid” before), a brief description was provided at the beginning of the interview (see Note S1 in the supplemental information). Participants were compensated with an electronic gift card. The University of Washington IRB approved all study procedures.

Table 1.

Demographic characteristics of interviewees (n = 67 across 63 interviews)

Relationship to donor	self	11 (16%)
	parent/caregiver	56 (84%)
Gender	male	10 (15%)
	female	57 (85%)
Race/ethnicity	White or Caucasian	54 (81%)
	Black or African American	3 (4%)
	Hispanic or Latino	2 (3%)
	Asian	3 (4%)
	two or more races	5 (7%)
Geographic region of residencea	West	26 (39%)
	South	17 (25%)
	Midwest	12 (18%)
	Northeast	10 (15%)
	non-US	2 (3%)
Donor diagnosis/genetic liability	autism spectrum disorder	22 (33%)
	Joubert syndrome	28 (42%)
	neurologic disease	6 (9%)
	none	11 (16%)

Note: A total of 67 people participated in 63 interviews; one interview was an adult donor with parent, one was with an adult donor and both parents, and one was with two parents.

^aGeographic regions are based on state groupings used by the US Census Bureau.

Acceptability of broad consent for health-related brain organoid research

Participants had previously donated biospecimens for biomedical research (related to autism spectrum disorder, Joubert syndrome, or adult-onset neurogenetic disease) and felt positive toward brain organoid research for these purposes, using words like “exciting,” “amazing,” “cool,” and “fascinating.” Participants identified benefits of organoid research as an alternative to more controversial methods (e.g., using animal models or fetal tissue) and as a low-risk means to develop and test customized treatments. As one donor put it, “It’s amazing to think about trying treatments, not on a human being but in a dish instead and seeing how it works” (adult donor). Research to promote human health was much preferred over applications that could be considered “just for fun” or frivolous. As one participant noted, “I’m not trying to get a better mascara. I’m trying to find ways to help mankind” (parent).

Within the context of health research, participants were generally comfortable with providing broad consent. For example, 100% were comfortable with their sample being used to study other conditions: “As long as it’s for the betterment of medicine, I have no problem with it. If I could give permission one time to cover several bases, that’s not a problem” (adult donor). The majority of participants accepted deferring to research teams on what specific research was done with organoids, citing their own lack of relevant expertise—“Who am I? I have no idea. I mean, I did dissect a frog in high school, but I think that’s it” (parent)—or their trust in the research team/institution—“I’m 100% hands off … I have great faith in [hospital]” (adult donor). However, a few (<5%) noted that their trust would not necessarily transfer to other research teams who could someday use their samples: “I’m okay with [doctor] doing important research on my child’s cells. But if it was a different lab, I may feel differently” (parent).

Participants also understood that broad consent is practical and efficient; it conserves researcher time and allows for multiple studies to proceed from one donation. Those who felt less comfortable with broad consent offered creative alternatives (echoing those proposed in the literature; de Jongh et al., 2022; Boers and Bredenoord, 2018), including having a checklist of potential future uses in consent forms, approval of future uses by a panel of donors, or time-limited “lease” models of consent that could be periodically renewed.

Desire for ongoing engagement

The theme that emerged most strongly was a desire for ongoing engagement with the research team, driven by three primary motivations.

• (1)To learn the results of the research

All participants expressed a desire to receive information about study results and updates on research progress. Participants offered two primary reasons for wanting research results: first, because they would find it personally meaningful—“[it] makes me feel like I’m contributing to my own cure or treatment”—or meaningful to their children—“[Our daughter] may not have a verbal voice that she can share every single day like the rest of us. But her voice is contained in how the researchers are expressing and discovering advancements.” Second, participants described how sharing results would foster a better relationship between researchers and participants, which could help with both recruitment and retention and, thus, support the research agenda. As one parent put it, “I think it just keeps people interested and willing to contribute to science … I think I would be really upset if I found out that you had gone several steps beyond what we had thought without us knowing. But if you brought us along in the process and said, ‘what if we do this next step?’”

• (2)To allow transfer of decision-making authority over time

Given the possibility that brain organoids could continue to be generated from a single biospecimen for many years into the future, participants were asked about long-term use of organoids created from donated cells. Adult participants were comfortable with organoids from their cells being used after their death (as one donor put it, “I won’t need them”). However, the majority of parent participants (60%) felt that their child should assume decision-making authority and be consented for continued use of their samples when they reach age 18. As one noted, “It’s only fair to him, because making a decision at 12 and making a decision at 18 are very different. And I also think that, like, the science is moving so fast, that, you know, what was possible then, and what’s possible when he’s 18 could be very different things.” The preference for involvement of an 18-year-old child in decisions about use of organoids was shared by parents who reported that their child was likely to be too cognitively impaired in adulthood to provide independent consent (12%) and by those who wanted to be included in a shared consent process with their child at 18 (6%).

• (3)To ensure ethical boundaries are not crossed

Participants understood that future research with brain organoids may go in new directions and use new technologies not anticipated at the time of initial consent. Two-thirds of participants wanted to at least be notified about future uses of organoids that go beyond the scope of the initial study, and over half wanted the opportunity to provide permission for continued use of their sample. Explicit permission was desired by those concerned that some future uses of brain organoids could be objectionable: “It shouldn’t be assumed where I or anybody else is comfortable with drawing the line” (parent). Cloning was the most common spontaneous example offered of ethically unacceptable research. Some participants also drew boundaries around the level of sophistication of organoids, expressing discomfort with growing a full brain (“If they’re recreating my child’s whole brain, then I might have a whole different set of answers to all these questions”; parent) or developing organoids with abilities such as self-awareness, memory, or the ability to experience pain. As one parent put it, “I would hate to think of any part of her to be in pain. I come from a very traumatic background … and I work very hard, personally, to make sure that I don’t do any of those things to my children. And I would be sad if somebody else did it.”

How to engage donors in brain organoid research?

The strong desire for ongoing engagement expressed by participants is striking given the lack of guidelines for working with human donors beyond the time period of initial consent. For example, guidelines have been devised for returning clinically meaningful individual results in genomics research (Jarvik et al., 2014), but no standardized requirements for returning of overall research results or maintaining longitudinal contact with biospecimen donors have been developed. The resulting patchwork relies on individual labs/biobanks to address these complex issues as time and resources allow. Of note, practical limitations were acknowledged by participants—“Would labs have to hire somebody whose sole purpose is to continue the consent process and continue the education process with subjects?” (adult donor)—and some expressed that they wanted to learn results, but not at the expense of researcher productivity.

Suggestions for ongoing engagement that satisfy donor preferences without overburdening researchers were offered by participants. As one noted, “I think a lot of times, people are so worried about the delivery of the communication that they just don’t communicate at all. And so, you know, even something as simple as an e-mail or a newsletter … to keep people just in the loop.” Participants also recognized that research projects take many years to complete and were interested in getting interim reports even partway through a study—“maybe an update, even like 2 years after [sample collection] to just know that it is being used. And it’s not just sitting there, that your efforts did not go in vain” (parent). Participants reported that e-mail was their most preferred mode for getting updates, with a desired frequency of once or twice a year.

Implications for future research and policy

These data are, to our knowledge, the first evidence generated on preferences of biospecimen donors to brain organoid research. Interviewees were a self-selected group with limited sociodemographic diversity who had already donated biospecimens and agreed to participate in a follow-up interview, and so they may be more interested in ongoing engagement compared with other donors or to those unwilling to donate biospecimens for research. Acknowledging this limitation, their perspectives offer insight into what donors are likely to desire and value for their contributions to brain organoid research.

Our primary finding of donors’ desire for ongoing engagement is consistent with prior work investigating attitudes of biospecimen donors to intestinal organoid research (Boers et al., 2018). Additionally, two interview studies with patients (i.e., potential donors) found that interviewees perceived brain organoids as particularly ethically sensitive compared with other organoid types (Bollinger et al., 2021), and some voiced that their willingness to donate would be contingent upon maintaining decisional authority over brain organoids created from their cells via ongoing contact with research teams (Haselager et al., 2020). Alternative models of informed consent (e.g., dynamic or governance models) have been proposed that conceive of consent as an active, ongoing communication process with donors, and they may be particularly fitting for brain organoid research given the empirical data that we and others have collected on patient and donor preferences (de Jongh et al., 2022; Boers and Bredenoord, 2018).

Prospective measurement of donor engagement strategies is a critical next step to build on this donor preference data and to determine optimal use of time/financial resources for engaging donors in brain organoid research. Importantly, interview responses suggest that donors are not only interested in learning about final, peer-reviewed research products, but they are also interested in interim updates as experiments are progressing. Providing interim updates could increase public understanding of how science actually happens—sometimes slowly, sometimes with setbacks, sometimes changing course in response to new information—and potentially combat the tendency to “over-hype” both the promises and risks of brain organoid research (Presley et al., 2022).

The question of how to engage with biospecimen donors is one that individual research teams must address, but is also relevant to policy makers and funders who can consider whether to recommend/require such engagement and whether to allocate funds specifically for such efforts. Now is an important moment, while brain organoid technologies are still in their infancy, to address the tension between calls for increased transparency to promote public trust in science (Wolinetz and Collins, 2020) against regulations (US Department of Health and Human Services, 2017) that (unintentionally) incentivize researchers to use de-identified samples rather than undertake the administrative burden of interacting with human donors.

Conclusion

For research modeling aspects of individual human brains using donated biospecimens, it is particularly important for researchers working with donated biospecimens to recognize, as one participant put it, “this is coming from a person, this isn’t just a cell‬.” Determining appropriate procedures for broad consent and ongoing engagement is relevant to all biospecimen research; however, the need is particularly urgent for brain organoid research given the field’s focus on individual-specific pathogenesis/treatment and the move toward increasingly sophisticated models—of our most personal organ—that could cross ethical boundaries for donors. More interdisciplinary scholarship is needed to determine the most effective and resource-efficient means of engaging donors over time to ensure that brain organoid research can align with donor values.