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Series: Celebrating the Human Genome Project and Its Outcomes
Opinion
Towards a Human Cell Atlas: Taking Notes
from the Past
Rik G.H. Lindeboom ,
1,
*Aviv Regev,
2,4
and Sarah A. Teichmann
1,3
Comprehensively characterizing the cellular composition and organization of
tissues has been a long-term scientific challenge that has limited our ability to
study fundamental and clinical aspects of human physiology. The Human Cell
Atlas (HCA) is a global collaborative effort to create a reference map of all
human cells as a basis for both understanding human health and diagnosing,
monitoring, and treating disease. Many aspects of the HCA are analogous to
the Human Genome Project (HGP), whose completion presents a major mile-
stone in modern biology. To commemorate the HGP’s 20-year anniversary of
completion, we discuss the launch of the HCA in light of the HGP, and highlight
recent progress by the HCA consortium.
Building a Reference Map of the Human Body
In the past decade, new methods have emerged for single-cell genomics that have revolutionized
our ability to identify and characterize the cells that comprise complex tissues. With these tools at
hand, the HCA project was launched as an international collaborative effort to create comprehensive
reference maps of all human cells –the fundamental units of life –as a basis for both understanding
human health and diagnosing, monitoring, and treating disease [1]. The foundation for organizing
large-scale consortium efforts such as the HCA leads back to the HGP. To commemorate the
completion of the HGP 20 years ago, we lay out organizational considerations and the latest
progress of the HCA community.
Lessons from the HGP
The HGP was launched in 1990 as a scientific effort of unprecedented magnitude to create a
reference map of the human genome. The success of this ambitious project depended on an inter-
disciplinary approach that bridged teams specialized in computation, engineering, and biology, in
an international collaboration between institutions in the USA, Europe, and Asia. The focus on in-
ternational and interdisciplinary collaboration inspired numerous large-scale consortium-based re-
search ventures that followed, including the HCA initiative. Recognizing the broad importance of
ethics by dedicating 5% of its funding to ensure proper ethical practice and explore its societal im-
pact, the HGP contributed an important aspect that inspired many large-scale biological projects.
While it was not fully clear at the time of the launch how the HGP would succeed in its ambitious
goal, the focus on intermediate milestones and technology development eventually led to a finished
human genome reference 2 years ahead of schedule and with budget to spare. This achievement
underlines the importance of phasing long-term initiatives into graspable intermediate goals to re-
fine future plans and exploit the inevitable increase in throughput and resolution that technological
advances bring.
Organizing the HCA
Similar to the aim of the HGP to build a reference map of the genome, the goal of the HCA initiative
is to create reference maps that chart the cells in human tissues and organs. Building such maps
Highlights
The Human Cell Atlas (HCA) consortium
was founded as a collaborative and
open effort to create a reference map of
the cells in the human body.
Organizing a large-scale project such as
the HCA draws inspiration from the
Human Genome Project (HGP) that
was completed 20 years ago.
Significant progress has been made by
the HCA community, including profiling
more than 39 million cells from 15 major
organs to date.
The expected impact of the HCA is illus-
trated by its use during the coronavirus
disease 2019 (COVID-19) pandemic.
1
Wellcome Sanger Institute, Wellcome
Genome Campus, Hinxton, Cambridge,
UK
2
Klarman Cel l Observatory , Broad
Institute of MIT and Harvard, Cambridge,
MA, USA
3
Cavendish Laboratory, JJ Thomson
Avenue, University o f Cambridge,
Cambridge, UK
4
Current Address: Genentech, South
San Francisco,
CA, USA
*Correspondence:
rl21@sanger.ac.uk (R.G.H. Lindeboom).
Trends in Genetics, Month 2021, Vol. xx, No. xx https://doi.org/10.1016/j.tig.2021.03.007 1
© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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requires collaboration between research groups and institutes, so the HCA was launched as an
open international initiative. To maximize the benefits from collaboration and data sharing, the
HCA is organized as an open and community-driven venture with more than 2000 members to
date, and growing. Any scientist that shares its ambitions, goals, and values can become a mem-
ber at any point by registering online
i
.
To ensure scientific leadership and deep engagement from the broad scientificcommunity,
HCA’s working groups take on its core challenges
ii
, and include the Biological Networks, each
taking on a specific tissue, organ, or system, the Analysis Working Group, focused on computa-
tional and analytical challenges, the Standards and Technologies Working Group, focused on the
needed experimental assays. Notably, when creating a human reference resource such as the
HCA, it is essential to ensure an equal benefit is gained worldwide, to both the participating
scientists and the representation of humanity, requiring the incorporation of extensive diversity
in sex and ethnicity. HCA engaged in this goal early and in an ongoing manner through the Ethics
Working Group, and more recently the Equity Working Group [2].
The relatively late realization of the importance of data analysis in the HGP presented a bottleneck
for the HGP to construct a genome reference [3]. Learning from this past experience, the
continuous development of computational approaches has thus been a major area of focus of
the HCA community
iii
, where the Analysis Working Group –the first working group of HCA –is
dedicated to the key computational challenge of building and querying and atlas. While the
core product of the HGP was essentially a single DNA sequence, the multimodal and complex
nature of the data generated within the HCA will require a modular and multifaceted approach
to standardize, integrate, and share data. To this end, the HCA Data Coordination Platform
was established in 2017, and is under continuous development to accommodate standardized
processing and broad access to HCA data through both graphic and programming interfaces
iv
.
In addition, a burgeoning community of tertiary data portals now enable users to easily access
and analyze HCA data without the need for sophisticated bioinformatics expertise. Examples of
these portals include the cellxgene software [4], EBI’s Single Cell Expression Atlas
v
,the
Cambridge Portal
vi
, the Broad Single Cell Portal
vii
,andtheUCSCCellPortal
viii
, each offering
interactive access to datasets from a wide range of HCA studies, with distinct analysis features.
Other dedicated portals, such as the COVID-19 Cell Atlas
ix
, Developmental Cell Atlas
x
, and the
Human Tumor Atlas
xi
data portals, are HCA-related portals dedicated to specific aspects of
human biology and/or disease.
Unlike the single coordinated funding structure for the HGP, the HCA involves a more distributed
structure, reflecting the democratization of technology, computation, and growth of the biomed-
ical scientific community itself, especially in genomics and computational biology, over the past
decades. At the time of the HGP, only a few, large, and heavily funded centers could perform
the needed work, but both single cell genomics technologies and associated computation has
become much more broadly accessible, partly due to the innovation and efforts of HCA
members. As a result, the funding and organizational structure is distinct: scientists participate
in HCA irrespective of their specific funding source, many funders support atlas construction
activities, and HCA is allied with several formally funded consortia focused on specific aspects,
providing a scientific community open to all.
Progress towards a Draft of the HCA
The HCA has already made significant progress towards the goal set for the first draft of a cell
atlas –profiling the common cell types in tissues from the major human organs
xii
. Currently,
HCA scientists have profiled more than 39 million cells using suspension cell genomics from 15
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major organ systems, including for example 11.1 million nervous system cells, 5.8 million embry-
onic and fetal cells, 3.4 million lung cells and 7.2 million immune cells. These atlases also cover
important human diseases, including nearly 4.8 million cells derived from severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2)-infected individuals. These statistics are collected by the
HCA Executive Office through regular quarterly surveys of its members, and thus reflect data cur-
rently available in a multiple range of sources, including data consented for open access stored at
the HCA Data Coordination Platform
iv
, and HCA data generated under consent for data sharing
by managed or controlled access only, which are currently distributed across various databases
such as dbGAP, DUOS, and EGA. These cell counts also include unpublished datasets for which
the cell numbers have been shared with us by HCA members.
The data collected across HCA is leading to exciting scientific discoveries. For example, a recently
published cardiac single cell reference highlights the cellular heterogeneity of the atrial and ven-
tricular chambers, and gender-specific differences in the cellular composition of the heart [5].
The emerging lung atlas discovered a host of new cell types, from the ionocyte, a new cell type
expressing the cystic fibrosis gene CFTR [6], to endothelial cell subsets that may play a role in
COVID-19 [7]. The gut atlas is recovering many dozens of cell types in the small and large intestine
[8,9], including rare cells such as enteric neurons [10]. Similarly, multiple atlases of the human
liver, an organ historically known for its homogenous cell type composition, reveal heterogeneity
in epithelial progenitors [11] and provide broad insights in hematopoietic development that
occurs in the fetal liver [12]. Single-nucleus RNA-sequencing (seq) of the neurons of the cerebral
cortex uncovered extensive differences in the cellular composition and characteristics between
human and mouse models, highlighting the importance of generating a cell atlas for humans
[13]. A spatial cell atlas of healthy and diseased pancreas tissues reveals how the morphological
organization of this organ features cell-type-specific neighborhoods and unexpected cell–cell
interactions [14]. In the thymus, the dynamic cellular composition across the human lifespan
unraveled the development and repertoire of T cells and thymic stroma at unprecedented
detail [15]. Profiling the cellular composition of the maternal–fetal interface of the placenta
unveiled many regulatory interactions that govern the cellular organization during early human
pregnancy [16].
While the first steps towards a HCA are to create a reference of healthy cells, many efforts have
also already examined implications in disease. A human single-cell atlas of the lung has identified
novel epithelial cell types, including asthma-related cell populations [17], and similar atlases in the
gut have helped understand cells related to inflammatory bowel disease [8,9]. Charting the dy-
namic cellular composition of the fetal, pediatric, and adult human kidney has uncovered that pe-
diatric and adult kidney cancers originate from different and previously little-known cell types [18].
Systematic interrogation of tumor cell landscapes with complementary single-cell RNA-seq tech-
niques has furthermore enabled scientists to study single-cell biology at a pancancer scale [19].
Several cell atlases have detailed organ-specific subsets of tissue-resident immune cells
[5,12,15,18], underscoring the impact of spatial and environmental influences of cells for their
identity and function. In disease, the HCA approach has inspired dedicated initiatives such as
the Human Tumor Atlas Network [20], whereas efforts such as the Kidney Precision Medicine
Program (KPMP) are tackling multiple kidney diseases. Similarly, the COVID-19 pandemic
sparked a large-scale joint effort of HCA scientists to shed light on this new pathology at
single-cell resolution (see later).
Impact of the HCA
As highlighted earlier, contributions by the HCA community have already led to numerous insights
ranging from basic human physiology and fundamental biology to discoveries with direct clinical
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applications such as pinpointing disease-associated cell types and pathology-induced cell states
(Figure 1). Beyond these direct insights that individual studies bring, the long-term goal of the
HCA is to provide a comprehensive reference of the identities and characteristics of the cells in
ahumanbody(seeOutstanding Questions). The HGP provided a reference where biologists
could look up the origin of, for example, their isolated fragment of DNA, RNA, or protein, and
how this differed in a disease context. The HCA aspires to become a similar tool to accelerate
both fundamental and translational science. Equivalent look-ups for HCA will include determining
which cells express a gene of interest, what cell types are present in a tissue/organ, and which cell
types co-occur in close spatial proximity. In addition, key marker genes that identify a cell type of
interest can be derived from the HCA, which can be the starting point for numerous experimental
assays.
The impact of the HCA on understanding human disease was powerfully illustrated during the
dawn of the COVID-19 pandemic. To obtain early insights into the pathology of COVID-19, the
HCA community used the existing single-cell RNA-seq data in the atlas to study important as-
pects of viral infection and responses at single cell resolution [21]. This quickly led to a compre-
hensive overview of the cells and organs that express key viral entry genes, such as ACE2, and
are therefore susceptible to SARS-CoV-2 infection. HCA scientists have since turned to studying
samples from COVID-19 patients and deceased donors directly, to shed light on disease pathol-
ogy at the single cell and spatial level. This work presents a clear case-in-point of how the HCA will
be useful for biologists and society.
The HCA also holds a translational promise, where the cell atlas can be applied to a range of
medical questions related to, for example, disease mechanisms, diagnostics, regenerative
medicine, and drug discovery and toxicity (Figure 1). Here, the HCA can be used to identify
disease-associated cell phenotypes that represent drug targets, predict cell-type specific effects
and understand on-target effects in other cell types. In regenerative medicine, the cell atlas can
provide guidance on how to steer differentiation into desired cell fates. In the clinic, new
biomarkers for disease could be identified and interpreted at unprecedented resolution.
Disease mechanisms
Diagnostics
Drug development
Regenerative medicineReference for spatial and
molecular cell characteristics
Foundation for
future consortia
Human
Genome
Project
Trends
Trends
in
in
Genetics
Genetics
Figure 1. Schematic Overview of the Impact of the Human Cell Atlas (HCA). Different biomedical fields that are
expected to benefit from the HCA are highlighted around the HCA logo. These fields (indirectly) also greatly benefited from
the Human Genome Project, which has provided insights and inspiration for organizing and predicting the impact of
consortia such as the HCA.
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While the earlier-mentioned examples provide insights in the direct and future utility of the HCA,
we can take notes from other consortia such as the HGP to predict the longer-term future impact
of generating the HCA (Figure 1). The impact of the HGP was much greater than the direct discov-
eries about the human genome. With the genome reference as a basis, many new large-scale
consortia such as HapMAP, 1000 Genomes, GWAS, ENCODE, and TCGA/ICGC projects
were launched, resulting in unprecedented scientific achievements. We expect that the HCA
can have a similar impact, where the fundamental knowledge about the cellular organization of
our body will act as a foundation for future projects and consortia to investigate human physiology
and disease at even higher resolution and in the spatial context of the human body.
Concluding Remarks and Future Perspectives
As we progress towards a first draft of the HCA, exciting technological advances are enabling the
community to characterize cells at higher throughput, and in a more detailed and comprehensive
manner. While the cellular maps highlighted earlier are mostly based on single-cell RNA-seq,
these are now complemented with chromatin profiles, protein profiles, and spatial information.
Simultaneous measurements of multiple modalities in the same single cell,such as the proteome,
transcriptome, and epigenome, will greatly advance our understanding of cell identities and phe-
notypic characteristics.
As laid out in the HCA White Paper [22], the first draft of the HCA aims to profile 30–100 million
human cells from all major organs in ethnically diverse males and females. In addition to cell
suspension-based transcriptome profiling –which is currently the most mature technology to
profile cells for the HCA –these tissues will also be profiled with spatial profiling technologies to
map identified cell types onto the tissue architecture of the human body. Rapid developments
in the throughput and molecular resolution of spatial transcriptomics and other spatial profiling
methods have enabled the establishment of the spatial branch of the HCA.
Lastly, mirroring the advances in sequencing technologies at the time of the HGP, there is a
sustained dramatic increase in throughput of single-cell profiling techniques; a trend that will
allow HCA to reach its ambitious goal to profile and ultimately characterize billions of cells from
human organs in health, as a reference map of the human body.
Acknowledgments
We gratefully acknowledge Jennifer E. Rood for critical reading and editingof this manuscript, and all authors of HCA papers
that we have not been able to cite due to space constraints.
Declaration of Interests
In the last 3 years, S.A.T. has consulted for Genentech and Roche, and is a member of SABs of Biogen, GlaxoSmithKline,
and Foresite Labs. A.R. is a cofounder and equity holder of Celsius Therapeutics, an equity holder of Immunitasand was an
SAB member of Neogene Therapeutics, Thermo Fisher Scientific, Asimov, and Syros Pharmaceuticals until July 31, 2020.
Since August 1, 2020, A.R. is an employee of Genentech, a mem ber of the Roche group. A.R. is an inventor on multiple
patents to the Broad Institute in the area of single cell genomics. R.G.H.L. has no interests to declare.
Resources
i
www.humancellatlas.org/join-hca/
ii
www.humancellatlas.org/learn-more/working-groups/
iii
https://openproblems.bio/
iv
https://data.humancellatlas.org
v
www.ebi.ac.uk/gxa/sc/home
vi
www.cambridgecellatlas.org
vii
https://singlecell.broadinstitute.org/single_cell
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Outstanding Questions
What is the comprehensive compendium
of cell types and cell states in the human
body?
Are there differences in tissue architecture
between males and females (besides
reproductive tissues)?
Are there stereotypical patterns of
ageing in human tissues?
Can HCA data reveal new units of
tissue architecture (i.e., recurring 3D
motifs of cell types) that are hitherto
unappreciated?
Can HCA data reveal new, previously
unknown adult stem cells and pinpoint
regeneration occurring as part of ho-
meostasis within adult tissues?
How similar are immune, fibroblast,
and vascular lineage cells across
tissues and organs?
What is the impact of gradients of
signaling molecules (either proteins or
small molecules, including, e.g., oxygen
gradients) in development and in adult
tissues?
Are cellular responses to gradients and
other challenges (e.g., oxidative stress)
restricted to a single cellular compart-
ment or concerted across, for exam-
ple, immune, epithelial, and vascular
compartments?
viii
https://cells.ucsc.edu
ix
www.covid19cellatlas.org
x
https://developmentcellatlas.ncl.ac.uk
xi
https://data.humantumoratlas.org
xii
www.humancellatlas.org/publications/
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