Data sharing ethics toolkit: The Human Cell Atlas

Perspective

https://doi.org/10.1038/s41467-024-54300-3

Data sharing ethics toolkit: The Human

Cell Atlas

Emily Kirby

,AlexanderBernier

, Roderic Guigó

2,3

, Barbara Wold

Fabiana Arzuaga

, Mayumi Kusunose

,Ma

’

n Zawati

& Bartha M. Knoppers

Striving to build an exhaustive guide

book of the types and properties of

human cells, the Human Cell Atlas

’

(HCA) success relies on the sampling of

diverse populations, developmental st

ages, and tissue types. Its open science

philosophy preconizes the rapid, seamless sharing of data

–

as openly as

possible. In light of the scope and ambiti

on of such an international initiative,

the HCA Ethics Working Group (EWG

) has been working to build a solid

foundation to address the complexities

of data collection and sharing as part

of Atlas development. Indeed, a particu

lar challenge of the HCA is the diversity

of sampling scenarios (e.g., living participants, deceased donors, pediatric

populations, culturally diverse backgr

ounds, tissues from various develop-

mental stages, etc.), and associated ethical and legal norms, which vary across

countries contributing to the effort. Hence, to the extent possible, the EWG set

out to provide harmonised, internationa

l and interoperable policies and tools,

to guide its research community. This paper provides a high-level overview of

the types of challenges and app

roaches proposed by the EWG.

In recent years, members of the international research community

have mobilised to enable streamlined, international data sharing,

particularly in the context of open science initiatives. Open science is

broadly de

fi

ned as a movement which seeks to leverage new practices

and digital technologies to increase transparency and access in scho-

larly research

, and improve reproducibility and replicability of

research

fi

ndings

. Data sharing and access to resources (data, meth-

ods, publications) are important pillars of the open science movement,

and both aim to ensure rapid and equitable access to pre-competitive,

raw research resources

Following the rise of data-driven, infrastructure research and

global referencing initiatives such as the Human Genome Project

,the

International HapMap Project

, the 1000 Genomes Project

,the

Human Pangenome Project

and the International Cancer Genome

Consortium

, issues such as bene

fi

t-sharing, access to data and

inclusive participation, have been fundamental considerations of

research consortia. Large volumes of data are required to statistically

power analyses of common and rare diseases, often requiring impor-

tant data storage and analytical capacities (e.g. cloud computing,

centralized or federated platforms)

. Biomedical research shows pro-

mise because this volume of data can now be generated.

The Human Cell Atlas (HCA) is an ambitious project hoping to

uphold principles underlying open science and data sharing. Its goal is

to map gene expression and other molecular pro

fi

les of all cell types

and cell states, tissues, organs, and organ systems in the

‘

healthy

’

human body. The construction of this reference map will then

enable research into dysregulated cell states contributing to disease

and leading, eventually, to the identi

fi

cation of biomarkers and

potential therapeutic targets

. The impact of the initiative relies

both on diversity (donor/participant demographic and phenotypic

Received: 10 September 2024

Accepted: 6 November 2024

Check for updates

Centre of Genomics and Policy, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, McGill University, 740 Dr. Pen

eld, Suite 5200,

Montreal, QC, Canada.

Bioinformatics and Genomics, Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), Dr.

Aiguader 88, Barcelona, Catalonia, Spain.

Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.

Division of Biology and Biological Engineering,

California Institute of Technology, Pasadena, CA, USA.

Interministerial Comission on Advanced Therapies Ministry of Science, Technology and Innovation

-Argentina Godoy Cruz 2320. 4th Floor, Ciudad Autónoma de, Buenos Aires, Argentina.

Center for Integrative Medical Sciences, RIKEN. 1-7-22 Suehiro-cho,

Tsurumi-ku, Yokohama City, Kanagawa, Japan.

e-mail:

emily.kirby@mail.mcgill.ca

Nature Communications

| (2024) 15:9901

1234567890():,;

characteristics, tissue types, developmental stages, participating

regions/countries, etc.) and on the collaboration of scientists, research

donors/participants, and communities, in order to obtain the number

of cells and datasets required to understand what a reference cell type

and a cell state might look like

The HCA proposes to build a resear

ch infrastructure. It is not a

research project in itself as it does not directly recruit participants,

sample or analyse tissues. Rather, building the Atlas relies on the

contribution of scientists around the world, who agree to contribute

data from their own local research projects to this combined effort. As

part of the efforts, an Ethics Working Group (EWG) was created early in

the inception of the HCA. Given the scope of the initiative, the EWG did

not set out to weigh in or resolve all ethical and legal issues that may be

encountered by the HCA consortium or its members, nor did it provide

an exhaustive review of all normative frameworks governing the con-

tribution of data in all jurisdictions or countries involved. Rather, the

focus of the EWG was to assess the structural issues pertaining to

contribution to the atlas from pre-existing projects and data sharing in

the context of an international collaborative effort.

The composition of the EWG was carefully selected to encompass

approximately 18 members, including lawyers, ethicists, genomic sci-

entists, representatives of the main regional networks of the HCA and

knowledgeable on the breath of ethical issues expected to arise (e.g.,

data protection/privacy, human tissue sampling, deceased donors,

data sharing, developmental biology, paediatrics, open science and IP,

etc.). The core membership is supported by a dozen active observers

of the Working Group, whose role is to provide input on key scienti

fi

technical, and strategic funding initiatives and needs of the HCA. In

addition, the work of the EWG is also informed by other activities of the

HCA, including the work of the Equity Working Group, which speci

fi

cally works to engage the global community spanning diverse geo-

graphic and ethnic groups in order to drive inclusive representation

and participation and promote equal bene

fi

tfromtheHCA.

This paper provides a high-level overview of the principal ethical

and legal elements discussed by the EWG, in relation to data sharing

and the ethical governance of infrastructure science. It then describes

the tools and resources created by the EWG to assist the research

community in sampling cell tissues and contributing datasets to this

large-scale, collaborative effort. Finally, we propose some lessons

learned in the development of tools and guidance for international

collaborative health research, in the context of a fragmented interna-

tional normative ecosystem. The objective is to provide insight into the

role of advisory groups, such as the EWG, within international colla-

borative research. These groups often operate outside the realm of

systematic research but provide critical and timely resources to the

set-up and functioning of such initiatives.

A lay summary of this article in English and in other languages can

be found at:

https://zenodo.org/communities/hcaewg/

Overview of normative framework and ethical issues

Given the large-scale, international and collaborative nature of the

HCA, the EWG

fi

rst set out to identify areas of tension between existing

normative frameworks. Then, alongside the development of data

governance within the consortium, it developed tools to enable

widespread participation by scientists around the world in the creation

of the Atlas.

Biomedical research, especially -omics research, is governed by a

complex framework of policies, guidelines, laws, regulations and best

practices (together, these rules are referred to as a

‘

normative frame-

work

’

). Historically, international ethical policies and guidelines, such

as the World Medical Association

’

s(WMA)

Declaration of Helsinki

(2024), the Council for International Organisations of Medical Sciences

(CIOMS)

International Ethical Guidelines for Health-related Research

Involving Humans

(2017), and the United Nations Educational, Scien-

fi

c, and Cultural Organisation, Bioethics Programme

’

s (UNESCO)

Universal Declaration on Bioethics and Human Rights

(2005), have

proposed foundational principles for ethical conduct of research with

humans. Core ethical issues addressed across guidelines include, for

instance, the protection of human dignity, integrity, right to self-

determination (autonomy), privacy, and con

fi

dentiality of personal

information, which are implemented through practices such as eval-

uating the risks and bene

fi

ts of research, free and informed consent,

evaluation of research by an ethics committee, and measures to pro-

tect vulnerable populations.

More recently, a number of international policy documents have

built on the existing normative framework to account for the

increasing research collection, use and sharing of data derived from

human research, including health-related phenotypic data and -omics

data. These include, for instance, the WMA

’

Declaration of Taipei

(2016), the Global Alliance for Genomics and Health

’

s (GA4GH

)Fra-

mework for Responsible Genomic and Health-related Data

(2014), the

Organisation for Economic Co-operation and Development (OECD)

’

Recommendation of the Council o

n Human Biobanks and Genetic

Research Databases

(2009) and

Recommendation of the Council on

Health Data Governance

(2017), as well as the UNESCO

’

Recommen-

dation on Open Science

(2021). While these guidelines reaf

fi

rm the

fundamental principles underlying research ethics, a few key adap-

tions have been made in relation to the particular considerations

surrounding data governance, use and sharing, including the creation

of health databases, data management, privacy considerations, and

future/secondary uses of data, etc.

The HCA is distinctive from a research ethics perspective as the

applicable normative ecosystem governing data contributors and

users calls upon both guidelines related to foundational research

ethics, as well as more recent norms pertaining to the sharing of

health-related and -omic data. The EWG examined a number of topics

at the intersection of these norms.

International collaborative rese

arch & research ethics oversight

First, as an international, decentralised collaborative initiative, the

HCA evolves in a distinct ecosystem of ethical oversight. Many inter-

national bioethical norms approach collaborative research using a

‘

multi-centric research

’

model, whereby a common protocol is

reviewed by ethics committees at each participating site, who then

evaluate the project based on local requirements. However, the con-

tribution of data to the HCA is ensured through different research

projects in different countries, each with their own protocol. The HCA,

therefore, has little control over the ethical approval of contributing

projects and must rely on a patchwork of local approvals. This

decentralised model, while allowing for consideration of local cultural,

ethical or regulatory speci

fi

cities by ethics committees, can be dif

fi

cult

to navigate when building data-intensive infrastructures. In particular,

it has been noted that local committees after often ill-equipped to

evaluate data sharing and its implications, particularly as part of larger

initiatives

–

To account for this complexity, the EWG developed tools for

guidance and support to contributors to the HCA and their local ethics

committees (see Table

). A key objective was to streamline local

ethical reviews, and strike a balance between providing common

ethical elements within the HCA (e.g., core consent elements, infor-

mation on data governance/access, retrospective consent assessment

tools, etc.), while allowing local committees to independently assess

any additional considerations applicable in their own jurisdiction or

context (e.g., research with vulnerable groups or populations, reg-

ulatory requirement or models pertaining to tissue sampling, data

protection laws, etc.).

Sampling human tissue

Second, to create a map of the human body, different tissue sampling

scenarios must be envisaged. For instance, to understand how cells

Perspective

https://doi.org/10.1038/s41467-024-54300-3

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change and evolve throughout life, the entire developmental lifespan

must be adequately captured, from gametes, embryos, and fetuses to

children and adults

–

both living and deceased (some tissues cannot be

sampled from living donors)

. Even within a single jurisdiction, these

different types of tissue sampling populations call upon the applica-

tion of different sets of rules or policies

, including norms related to

consent, tissue acquisition, data/sample sharing or data protection

considerations

. This presents an important, but not insurmoun-

table, challenge to global projects such as the HCA, particularly in

relation to acquiring tissues at different life stages.

As part of early background normative research, the EWG

developed thematic

‘

primers

’

to identify and examine local practices

related to consent and data sharing across a number of different

jurisdictions representative of HCA regions

. As anticipated, this

work concluded that the way in which the interests of research par-

ticipants or tissue donors are protected, as well as their level of

protection, are culturally speci

fi

c and vary across countries

.Asan

example, while the universal requirement of free, informed consent

ensures that research respects individual autonomy and choice, how

this essential requirement is satis

fi

ed varies across jurisdictions and

across tissue acquisition scenarios. Examples of this variation include

the recognition (or not) of models such as:

“

opt-in

”

; free, informed

consent; consent to secondary uses; broad consent; presumed con-

sent (opt-out); or waivers

A challenge for the HCA EWG was, therefore, to identify the type

of tools (e.g., consent form models, guidance for recruiters) needed to

guide data contributors in relation to the complex task of assembling

‘

interoperable

’

global, dataset, while recognising and respecting the

wide range of ethical provenance related to tissue acquisition. Practi-

cally speaking, in some instances, this meant providing variations of

the same template or document, to account for different regional

models (as an example, post-mortem tissue donation is considered a

‘

gift

’

in certain jurisdictions, while in others, it remains human research

requiring research consent

–

and therefore, different templates were

proposed).

Data protection and privacy considerations

Third, data protection and privacy considerations related to genomic

data, particularly in relation to technological innovations, are rapidly

evolving. As mentioned, not only have research ethics norms been

adopted speci

fi

cally for the sharing and use of health data, but the

increased global scrutiny surrounding the protection of personal data

has also had an important impact on data sharing for research

purposes.

In this context, an important question for the HCA was to assess

whether data incorporated in the atlas and subsequently shared

(including phenotypic metadata as well as data derived from single

cell sequencing technologies), constitutes personal data, as de

fi

ned

under several data protection regimes. This determination would

then have important repercussions for the different stakeholders of

the consortia, given their role as potential data processors

Although this discussion was initially instigated by the entry into

force of the General Data Protection Regulation

, it rapidly became

apparent that this analysis would be relevant to other jurisdictions

with similar protection regimes for data considered personal or

identi

fi

able. Ultimately, and similarly to other health research

consortia

, a pragmatic approach was adopted whereby an ongoing

assessment of data types (e.g., gene count matrices, sequencing data,

metadata) and proportionate governance models were implemented

(e.g., controlled or managed access)

while proposing a release of

appropriately consented data in open access when possible. This

approach was then described in the Ethics and data governance

document proposed in the toolkit (Table

and Fig.

), to convey the

model to bodies such as research ethics committees and institutional

representatives, ultimately authorising data contribution.

Open science, data sharing, access and use

Fourth, data sharing and open science have increasingly been dis-

cussed in the context of infrastructure science. The concept of

‘

open

science

’

has been widely used to refer to several components of the

research endeavour

–

including intellectual property, publication, and

access to resources (such as data, protocols, tools and methods).

Sectoral guidelines such as the FAIR

and CARE

principles and the

GA4GH

Framework for Responsible Sharing of Genomic and Health-

related Data

, have proposed frameworks to foster data discovery,

accessibility, interoperability and re-use. While the HCA

’

s activities

relate to several facets of open science, the HCA EWG was more spe-

fi

cally involved in examining open science in the context of data

sharing.

On the one hand, open data sharing strives to enable unencum-

bered, rapid access to greater sample sizes, fostering large-scale ana-

lyses, replicability and transparency

. Advocates of open science

have emphasised the potential

fi

nancial impact of openly sharing data

resources through broader access, particularly for researchers and

institutions in low-income settings and citizen scientists. On the other

hand, if not adequately implemented, open data sharing can fail in

reaching its objectives and, in some cases can cause unintended harm.

For instance, there are privacy concerns with sharing some types of

Table 1 | Overview of the categories of to

ols developed for the HCA ethics toolkit

. The full toolkit is available online at:

humancellatlas.org/ethics

Category

Description/purpose

General Ethics and Data Governance

Explain the HCA project in simple terms, providing useful background documents for institutional ethics review c

om-

mittees tasked with approving the collection of tissues and the contribution of data to the HCA

Consent tools

Templates and assessment tools for different HCA sampling scenarios (adult participants; addendum to consent forms for

sampling of clinical leftover tissues; consent template for deceased donors; templates for the collection of developmental

tissue samples; consent

lter assessment tool for legacy datasets)

A paediatric portfolio is available alongside the main consent tools to address certain issues speci

c to the paediatric cell

atlas, including templates for the assent of minors as well as the consent of mature minors/parents/legally authorised

representatives.

Data submission and sharing

between sites

Template Material/Data Transfer Agreement, which incorporates key elements speci

c to the HCA, particularly with

respect to open data sharing.

Policies for the implementation of a managed access tier for certain datasets.

Implementation of a Data Access Compliance Of

ce (DACO) and Data Access Committee (DAC) (including imple-

mentation procedures)

Additional tools

Background reading material on the following topics:

‘

Building the Human Cell Atlas: Issues with Tissues

’

‘

Children

’

Right to Health

’

,and

‘

Children

’

s Data Protection

’

Ethics Helpdesk

Helpdesk for the HCA community to submit questions and to ask for certain topics to be brought to the attention of the

HCA EWG

Perspective

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Nature Communications

| (2024) 15:9901

data publicly (even if permissible under data protection laws and

appropriately consented). Furthermore, because there is less control

and visibility of how the data is being accessed and used, there is a

potential for use that could be considered inappropriate and could

result in harm to groups/communities (e.g., stigmatisation)

,indivi-

duals (e.g., linkage with external datasets, re-identi

fi

cation attempts,

discrimination), or society (e.g., data scraping/harvesting and use of

arti

fi

cial intelligence algorithms for future unknown analyses, etc.).

In the case of the HCA, it also became apparent that imposing an

‘

all or nothing

’

approach to open data sharing might actually impede

researchers from certain regions or groups from contributing data to

the atlas, particularly where more conservative regulatory regimes

exist, or where cultural, ethical norms or donor consents limit public

sharing of data

. This tension is also apparent in frameworks where

data sovereignty and authority over data is central to equitable parti-

cipation, for instance, in the context of sharing data from Indigenous

Communities

. Ultimately, inappropriate implementation of open

science could lead to inequities in the representativity of the atlas and

diminish its scienti

fi

c value and collective bene

fi

In practice, data sharing proposes a spectrum ranging from con-

trolled (or managed) access data to open (or public) data. Given that

the HCA strives to uphold open science principles, ongoing discus-

sions between a number of HCA stakeholders (including data con-

tributors, the HCA Data Coordination Platform, the EWG and the

Organising Committee) were centred around adopting processes and

infrastructure to enable as much sharing of open (public) data as

possible while recognising the need to protect and govern certain

datasets under managed access. Again, through discussions with the

HCA community, these decisions and processes were translated into

various documents of the ethics toolkit (such as the Ethics and data

governance and consent templates) so as to replicate and disseminate

this information throughout the data lifecycle (consent, contribution,

storage, sharing).

Building the HCA ethics toolkit

To develop a common approach to data sharing within the

consortium

and to navigate the ethical and legal landscape

described above, the EWG strived to develop practical guidance and

tools (Table

). These needs were addressed throughout the research

data lifecycle, engaging with potential HCA scienti

fi

c stakeholders in

the process

–

from recruitment/collection of tissue samples to storage

and analysis within the HCA Data Coordination Platform (DCP), and

fsh/sharing (see Fig.

For data contributors and their institutions, guidance was needed

around consent language and providing explanatory materials for

tissue sampling sites to enable contribution to the atlas (particularly

with respect to open access data). Streamlined, high-level explanations

regarding the structure and governance of the HCA were also needed

to guide local ethics committees in their understanding of the initia-

tive. The HCA consortium itself, particularly the DCP, called upon the

Internaonal (norms, guidance, declaraons, etc.)

Country/regional (laws, direcves, regulaons, policies, etc.)

Local (instuonal policies, guidance, requirements etc.)

(I) Normave ecosystem

(II) Human Cell Atlas

Ethics Toolkit

www.humancellatlas.org/ethics

...collecvely inform the development of the:

Data Contributors:

Tissue collecon

& data generaon

Data Wranglers and HCA Data Coordinaon

Plaorm:

Data upload / ingest

Data Users:

Accessing

data

Ethics and data governance document

Ethics commiee FAQs

Consent tools

Templates and assessment

tools for different HCA

sampling scenarios

Pediatric porolio

Tools for data submission and sharing between sites

Template agreements, managed access tools, DPIA template, etc.

(III) Key stakeholders

within the HCA scienfic

community

Fig. 1 | The ecosystem underlying the construction of the HCA ethics toolkit

and its key HCA community stakeholders.

This

fi

gure provides an overview of the

ecosystem underlying the construction of the HCA ethics toolkit and its key HCA

community stakeholders.

(I) Normative Ecosystem

.Thetopofthe

fi

gure depicts

the sources of policies, norms and regulations that inform how tissues and data can

be collected and shared, for contribution to international efforts such as the HCA.

(II) Ethics Toolkit

. In turn, these rules informed the development of different tools

proposed in the HCA ethics toolkit which are publicly available at humancellatla-

s.org/ethics (blue rectangle). Different tools proposed are intended for different

stakeholders of the HCA community. For instance, the

‘

Ethics and data governance

document

’

and the accompanying

‘

Ethics committee FAQs

’

are intended to provide

an overall description of the HCA, its data platforms and data release model in

language that is accessible to data contributors, and their local ethics committees.

These documents are also relevant to other HCA stakeholders as they have been

developed by engaging different groups, including platform developers, data

wranglers, and potential users (as depicted by the blue arrows). Consent tools are

mainly intended for contributors to the HCA (as depicted by the blue arrows). The

EWG engaged with speci

fi

c contributor communities for sector-speci

fi

c guidance,

for instance, in the areas of paediatrics, developmental tissues, or clinical sampling.

Finally, tools related to submission and sharing between sites are of particular

use to both data wranglers as well as data users (as depicted by the blue arrows).

(III) Key Stakeholders

. As the atlas is developed, we will continue to pilot different

tools (e.g., data sharing and contribution agreement templates) through engage-

ment with these stakeholders within the HCA community, and monitor whether

adjustments are needed.

Perspective

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EWG to provide input on data protection matters and data sharing

within an open science context. Liaison with other similar data-sharing

initiatives with existing ethical frameworks

–

including speci

fi

c pro-

jects (e.g., GTEx) and standards organisations (Global Alliance for

Genomics and Health (GA4GH))

–

ensured that the tools developed for

the HCA remain anchored into the existing data and policy ecosystem.

Indeed, the EWG must work towards the goal of interoperability

between existing and future initiatives, in the spirit of fostering (re)use

of datasets

Proposing practical tools to address the ethical needs of the HCA

research community was an important step to fostering pragmatic,

actionable approaches to data sharing within the Atlas. While this

article can only provide a high-level overview of the different facets of

the ethics toolkit, we invite readers to learn more about the underlying

approach proposed for each tool by consulting the publicly accessible

resources available at:

www.humancellatlas.org/ethics

The

‘

-omics

’

research community has long been advocating for

the development of tools and standards to harmonise approaches to

data sharing

–

. Organisations such as the GA4GH work to enable

responsible sharing of clinical and genomic data through both policies

and harmonised data aggregation and federated approaches, to

advance genomics medicine and research

. The HCA is a driver pro-

ject of the GA4GH, meaning that it is an initiative that shapes GA4GH

products and applies them to real genomic data

. The tools in the HCA

Ethics Toolkit were inspired by both the GA4GH Framework for

Responsible Sharing of Genomic and Health-related Data

and by

policies developed by the GA4GH Regulatory and Ethics Work Stream

(REWS), in an effort to harmonise HCA practices with other global

-omic initiatives

–

Lessons learned: building large-scale research infrastructures in

a fragmented normative environment

Developing actionable guidance for researchers to contribute to large-

scale initiatives can encourage participation across contexts and

regions despite differences in normative frameworks. We argue that

these ethics and policy tools are representative of broader socio-

cultural and policy issues that a number of international data-sharing

research consortia must contend with refs.

–

. Learning from the

HCA EWG experience, we propose that the development of ethics and

policy tools for collaborative data sharing should attempt to foster: (1)

interoperability, (2) scalability/

fl

exibility and (3) actionability.

In the

fi

eld of biomedical research, interoperability is generally

fi

ned as enabling the meaningful comparison and combination of

data across different research efforts or research sites

.Achieving

interoperability (or a certain degree of harmonisation), is essential to

the scienti

fi

c endeavour, particularly in the context of international

collaborative research consortia, which ultimately rely on the con-

tribution of members (and member projects)

. Ethical and legal rules,

standards or policies are a potential source of heterogeneity in

datasets

and can limit or place conditions on the contribution of

data to the consortium as well as on further data sharing by the con-

sortium. Interoperability can therefore be achieved by working on the

architecture of the consortium upstream of data contribution (for

example, by making template consent language, available to con-

tributors, by proposing different models based on known regional

variations), to ensure that entering datasets are suitable for further

sharing as envisaged.

As an example, a review across seven countries of approaches to

consent to tissue sampling for research use, undertaken as part of HCA

EWG work, found that while there was a universal requirement of free,

informed consent, the implementation of this essential requirement

varies in different countries (the traditional

“

opt-in

”

model to free,

informed consent, as compared to consent to secondary uses, broad

consent, presumed consent (opt-out), and waivers)

. Moreover, even

where there are high-level commonalities between jurisdictions, key

differences remain that are speci

fi

c to types of tissues and of research

(for instance, embryonic/foetal tissue, paediatric or adult)

, particu-

larly in more culturally sensitive research areas (e.g., developmental

biology). Given this diverse context, we identi

fi

ed key thematic areas

where normative commonalities could be identi

fi

ed, particularly in

light of international guidelines.

In the context of the HCA, interoperability efforts were integrated

in a number of consent tools designed for data contributors. For ret-

rospective datasets, which include datasets generated from legacy

tissue samples (e.g., archival samples, samples collected for a purpose

other than research, etc.) and datasets that were generated before the

creation of the HCA, an assessment tool was developed for con-

tributors to determine whether datasets are suitable for inclusion in

the HCA. This assessment is based, amongst others, on the source of

the tissue sample, the donor consent to broad international data

sharing, the donor consent for open data sharing, and/or whether

reconsent/waiver of consent is feasible

. For prospective datasets -

meaning datasets to be speci

fi

cally consented for use in the HCA - core

consent elements

were proposed. These minimal clauses should

explain particularities surrounding the generation of research data

from tissue samples, international sharing, future use, commercial use,

public (open) access, storage on cloud servers, duration of storage,

data withdrawal and re-identi

fi

cation.

In addition to fostering interoperable datasets, the ethics toolkit

was developed as a scalable model, meaning that it can be adapted to

use across different data contribution and access scenarios. Because of

the vast differences in normative frameworks in the different jur-

isdictions likely to contribute data to the HCA, it was dif

fi

cult for the

EWG to impose a single approach (all-or-none open data) without

trading off the scienti

fi

c value of the data collection. The EWG, there-

fore, did not impose normative decisions but rather, worked to create

adaptable tools that could accommodate as many options as possible

(e.g., different tissue sampling sources, consent models, etc.). A lim-

itation of scalability, however, could be that contributors eventually

deviate from the models proposed (for example, in adapting their own

local consent forms). Further re

fi

nement and revision of the current

tools proposed could be envisaged through additional consultation

with stakeholders and toolkit users, by compiling and analysing

changes made to existing templates once the

fi

rst version of the toolkit

has been in use for a certain period of time.

The notion of scalability was also particularly central to the EWG

’

discussion on open and controlled access data. While open science is

central to the HCA

’

s mission, in light of the international regulatory

landscape, it quickly became apparent that achieving open access data

(i.e., public data) globally would be a daunting task. Furthermore, a

‘

one-size-

fi

ts-all

’

approach to public data sharing could also inad-

vertently exclude certain regions, populations, or groups from con-

tributing to the HCA because, for instance, of data protection

regulatory requirements, ethical policy, or cultural sensitivities

–

In response to this ongoing discussion and consultation of stake-

holders within HCA leadership, the EWG integrated language

throughout the toolkit (e.g., consent form templates, explanatory

documents for ethics committees, material/data transfer agreements)

to make the toolkit materials adaptable to the public release of

data, while recognising that some datasets may require con-

trolled (or managed) access. This approach allowed for immediately

populating the HCA public database, while acknowledging that some

contributors would need additional technical infrastructure to con-

tribute their data responsibly.

Finally, a key element to ensure that contributors to the HCA and

its users are implementing the available ethics resource is that doc-

umentation be readily actionable and implementable. Ethical and legal

requirements can often seem distant from the realities of scienti

fi

research. Research, in turn, can sometimes seem overly technical or

theoretical for the lay community. However, the success of an

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infrastructure initiative such as the HCA relies on building a common

understanding between different stakeholders involved, including

donors/research participants, communities, ethics committees, reg-

ulators, scientists, and funders

. In the context of the HCA, this meant,

for instance, providing accessible explanation regarding the technol-

ogy used (e.g., single-cell RNA sequencing, cellular pro

fi

ling), but also,

of concepts surrounding data sharing (open, controlled, etc.). The

ethics toolkit was developed with this premise in mind, and in parallel

to other HCA initiatives (public engagement, equity, diversity, and

inclusion). For instance, language was carefully adapted to the proper

audience (e.g., explanation to research ethics committees, consent

documentation for donors/participants, explanation to regulators/

lawyers, etc.).

In sum, the path to building an interoperable, scalable, and

actionable ethics governance framework for the HCA involved

assembling a multidisciplinary working group, supported by strong

integration within the HCA technical and scienti

fi

c communities. The

efforts of the also closely align with those of other HCA initiatives, such

as the HCA Equity Working Group, as these groups strive to ensure that

the Atlas is built for the bene

fi

tofhumanity

. Early commitment and

support from HCA leadership were key to building a sound ethics

governance framework, in synergy with the development of the Atlas,

allowing for actionable implementation of foundational data sharing

premises

through resources for the scienti

fi

c community contribut-

ing to the consortium. In time, however, we expect that further

fi

nement, revision or adaption of the toolkit may be necessary,

particularly as the data-sharing landscape evolves (for instance, due to

technological changes, changes in the regulation of data protection,

research ethics, use of arti

fi

cial intelligence, etc.). This may require, for

instance, re

fi

nement of consent wording, sharing agreements, or

adaptation to data governance arrangements. This is a potential lim-

itation of the current work, however, it may become an opportunity to

further engage and consult active HCA contributors, developers

and users.

Building on a number of key Open Science principles set forth

by UNESCO in 2021, in order to develop a global public good ben-

fi

tting humanity, careful consideration must be given to concepts

such as: access, data, software and hardware, infrastructures, eva-

luation, educational resources, engagement of societal actors, and

diversity of knowledge

. Doing so relies on the ability of the con-

sortium members and stakeholders to operate within clear, imple-

mentable policy environments, to build sustainable and inclusive

research infrastructures. It also calls for ongoing monitoring of

emerging issues and an agile response to adapt the ethical frame-

work to rapidly evolving social, scienti

fi

c, and technological

environments.

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Acknowledgements

The co-authors wish to thank all members and observers of the Human

Cell Atlas Ethics Working Group for

their ongoing contributions and

collaboration. B.M.K., A.B. and E.K. are funded by the Chan Zuckerberg

Initiative, the Klarman Family Foundation, and a grant from The Leona M.

and Harry B. Helmsley Charitable Trus

t to McGill University. M.Z. would

like to acknowledge the contributi

on of FRQS through the J1 Career

Award. This publication is part of the Gut Cell Atlas Crohn

’

sDisease

Consortium funded by The Leona M. and Harry B. Helmsley Charitable

Trust and is supported by a grant from Helmsley to McGill University.

www.helmsleytrust.org/gut-cell-atlas/

. This publication is part of the

Human Cell Atlas

–

www.humancellatlas.org/publications/

Author contributions

E.K. drafted the original manuscript and coordinated the work of the

HCA EWG. A.B. assisted in the development of tools for the EWG. R.G.,

B.W. and B.M.K. supervised the work and co-chaired the HCA EWG. F.A.

and M.K. are members of the EWG and

contributed to the development

of EWG tools. M.Z. is a current co-chair (2024) of the EWG and a member

of the HCA Inc. Board of Directors. B.M.K. is a member of the HCA

Organising Committee. All co-authors reviewed and edited the

manuscript.

Competing interests

The authors declare no competing interests.

Additional information

Correspondence

and requests for materials should be addressed to

Emily Kirby.

Peer review information

Nature Communications

thanks the anon-

ymous reviewers for their contribution to the peer review of this work.

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is available at

http://www.nature.com/reprints

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