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On the Journey from Nematode to Human, Scientists Dive by the Zebrafish Cell Lineage Tree Ehud Shapiro

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On the Journey from Nematode to Human, Scientists Dive by the Zebrafish Cell Lineage Tree Ehud Shapiro Shapiro Genome Biology (2018) 19:63 https://doi.org/10.1186/s13059-018-1453-x RESEARCH HIGHLIGHT Open Access On the journey from nematode to human, scientists dive by the zebrafish cell lineage tree Ehud Shapiro no further information on the nature of the cells, and hence Abstract rather uninformative. To label the tree with cell types, tran- Three recent single-cell papers use novel CRISPR-Cas9- scriptomic (or other) analysis of each cell is needed in sgRNA genome editing methods to shed light on the addition to its genomic analysis. While single-cell tran- zebrafish cell lineage tree. scriptomicsisprogressinginleapsandboundsandisnow the cornerstone technology of the international Human Cell Atlas project, integrated single-cell genome and tran- Whole-organism cell lineage tree scriptome analysis is still in its infancy [2]. The cell lineage tree of the nematode Caenorhabditis Fortunately, a new idea has recently emerged. It is pos- elegans was uncovered four decades ago by painstaking sible to use CRISPR-Cas9-sgRNA genome editing to ad- ’ observation of the nematodes development. The tree, typ- dress these two problems simultaneously. In accordance ically drawn upside-down, has the root at the top, repre- with the multiple discovery theory, the idea is presented in senting the fertilized zygote, the leaves at the bottom, three independent, almost simultaneous, publications, all ’ representing the organisms extant cells, and internal applying it to the discovery of the zebrafish cell lineage branches representing past cells that have divided. Cell tree [3–5]. lineage trees are typically labeled with the types of the cells Uncovering zebrafish cell lineages by scarring its gen- and, in the case of the small (959 somatic cells) and deter- ome, waiting, then fishing the scars, the method uses ministic cell lineage tree of C. elegans, also with a unique CRISPR-Cas9 to inflict random edits to the cell’s gen- identifier for each cell. This Nobel-winning work has been ome, called genomic scars, at specifically chosen subge- the bedrock of ample research on C. elegans biology ever nomic (sgRNA)-guided locations. Such scars are, in fact, since. induced somatic mutations heritable via cell division and Unfortunately, science has yet to know the cell lineage can be used, with the help of phylogenetic analysis tools, tree of a more complex model organism. Mathematically, to reconstruct lineage relationships among the organ- naturally occurring somatic mutations induced during nor- ism’s scarred cells. As the putative locations of these mal cell division carry enough information to specify with scars within the genome are known, they can be recov- high precision the organismal cell lineage trees of complex ered by targeted sequencing, eschewing the need for organisms, such as mouse and possibly even human [1]. high-coverage single-cell whole-genome sequencing. To Utilizing phylogenetic analyses of naturally occurring som- eliminate the need for simultaneous genomic and tran- atic mutations for the discovery of cell lineage trees faces scriptomic analysis of individual cells, these scars are two major limitations at present. First, eliciting this muta- inflicted in expressed genomic loci. Thus, single-cell tional information, such as by high-coverage single-cell RNA sequencing can recover both a cell’s type and its whole-genome sequencing of every cell of a complex or- expressed genomic scars. To ensure the scars do not ’ ganism, is prohibitive with todays technologies. Second, affect organism development, they are applied only to a such a tree, obtained solely from retrospective phylogenetic nonfunctional transgene such as GFP, which is incorpo- ’ analysis of the organisms extant cells, would be blank, with rated in a sufficient number of copies in the genome to support ample scarring. Three variations of this Correspondence: [email protected] combined concept, termed ScarTrace [3], scGESTALT Department of Computer Science and Applied Math, Weizmann Institute of [5], and LINNAEUS [4], have been applied by the three Science, Rehovot, Israel © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shapiro Genome Biology (2018) 19:63 Page 2 of 3 teams to analyze various aspects of the zebrafish cell and leaves of an organismal cell lineage tree are deter- lineage tree, focusing on early development [4], the mined by the actual experiment that generated it, time- brain [5]andtheentireorganism,withfocusonthe stamps of internal nodes can only be inferred immune system and eye [3]. Highlights of their re- retrospectively, like type and location information, with search findings include showing that a subpopulation the aid of yet-unavailable mathematical methods applied of resident macrophages in the fin has a different ori- to snapshots taken at different time points. gin than monocytes in the marrow [3]; that erythro- Sixth, a fundamental limitation of any retrospective cytes generated by primitive hematopoiesis have a method, including this one, is that it cannot peer distinct origin from those generated by definitive into the past, only speculate about it. Specifically, hematopoiesis [4]; and that the heart harbors two single-cell RNA-sequencing can provide information seemingly very similar endocardial/endothelial cell only on extant cells, namely the leaves of the cell types which have very different origins [4]. lineage tree. Any knowledge on past internal tree nodes can only be inferred. Conversely, analysis of Diving deeper into the zebrafish cell lineage tree an organism at cellular resolution using current The research milestone reached by these three papers is methods requires its sacrifice, obviously preventing worth celebrating, as it offers a completely new way to further organism development, so peering into its fu- peer into complex organism development. Yet, it is a ture is also impossible. If organism development is small step in a long journey. Even within the realm of deterministic, as in C. elegans, internal nodes can be zebrafish, many limitations have yet to be overcome. analyzed by freezing development of individuals at First, the number of cells analyzed by these papers is different time points for analysis, and then coales- measured in the tens of thousands, a far cry from the cing the resulting partial lineage trees into a unified adult zebrafish estimated 100,000,000 cells. Significant lineage tree. However, complex organisms may not scaling of the method in all dimensions, as well as dras- be deterministic, in which case simple coalescence of tic declines in sequencing costs, is needed to reconstruct cell lineage trees, even of clones, might not be pos- the full zebrafish cell lineage tree. sible. Snapshots at cellular resolution of different in- Second, unlike natural somatic mutations, which dividual organisms at different stages of development occur continuously during normal cell division, the would be needed and helpful of course, but they methods described inflicted CRISPR-Cas9 scarring cannot be simply coalesced. Yet-unavailable mathem- only once or twice during the organism’s lifespan. atical and computational methods have to be devel- Continuous scarring is needed for full cell lineage tree oped to make sound inferences of the type and reconstruction. location of internal nodes from information on the Third, while phylogenetic analysis tools have been im- cells at the leaves of a cell lineage tree of a complex proving for decades, phylogenetic cell lineage recon- organism. struction has specific needs, notably coping with noisy, partial, or missing single-cell genomic data, and recon- structing ever-increasing lineage trees, orders of magni- From zebrafish to mouse and—ultimately—to the tude larger than what has been previously attempted. human cell lineage tree Novel and better algorithms have to be developed to Climbing up the model organism hierarchy, the cope with these challenges. mouse is an obvious next target of this method, as a Fourth, while cell type and lineage are useful informa- lot of cell lineage knowledge exists as a backdrop to tion, without cell location the resulting picture would verify the method, as well as to improve upon. The still be rather partial. Methods for in situ RNA sequen- mouse can also be a stepping stone for human cell cing which could incorporate genome scarring to un- lineage reconstruction. A key hurdle for any human cover simultaneously cell location, cell type, and cell cell lineage reconstruction method is lack of a ground lineage would give a more complete picture of organism truth to measure against. While a cell lineage tree development. can be easily scribbled, verifying its relationship to Fifth, while the number branches between a cell and the actual developmental history of an organism is far the root measures the number of cell divisions it under- from trivial. If and when genome scarring proves a went since the zygote, it does not measure time. There reliable method for mouse cell lineage reconstruction, could be parts of the tree that extend slowly throughout it can serve as a ground truth for testing, in mouse, the adult life and parts that progress quickly during early retrospective cell lineage reconstruction using natur- life then stop. The timing of cell division, differentiation, ally occurring somatic mutations. Due to ethics con- and renewal is a major question of fundamental bio- siderations, this may be the only viable method for logical importance. While the timestamps of the root uncovering the human cell lineage tree. Shapiro Genome Biology (2018) 19:63 Page 3 of 3 To conclude, let’s ask: why bother? What will we 8.
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