The Initiative

Mission
The unifying goal of the Human Cell Lineage Flagship initiative is to develop a high-throughput, large-scale, accurate, multidisciplinary, science-driven, collaborative cell lineage analysis infrastructure and apply it to uncover the structure and dynamics of the Human Cell Lineage Tree in health and in disease.

Mission Rationale
Central open problems in biology and medicine are in effect questions about the human cell lineage tree: its structure and its dynamics in development, growth, renewal, aging, and disease. Consequently, knowing the Human Cell Lineage Tree would resolve these problems and entail a leapfrog advance in human knowledge and health.

When cells divide each of the two daughter cells accumulate a small number of random mutations. These random somatic mutations accumulate independently in each body cell, and constitute an effectively unique "genomic signature" for each body cell. Our Human Cell Lineage Tree is implicitly encoded by the genomic signatures of our body cells, as cells with similar signatures must reside near each other in the cell lineage tree and cells with very different signatures must be far from each other, much the same way as people with very similar genomes must be near each other in the human family tree. Hence uncovering the genomic signatures of human body cells will reveal the Human Cell Lineage Tree. As reconstructing a cell lineage tree utilizing somatic mutations is non-invasive and retrospective, it is ideally suited for the study of human development, growth, renewal, aging, and disease.

Therefore, the proposed Human Cell Lineage Tree Flagship initiative is to build a collaborative cell lineage analysis infrastructure by a large federated multi-disciplinary effort of leading partners in ICT and biotechnology; to engage a large number of leading research groups in a wide range of branches of biology and medicine to resolve key open problems using this collaborative infrastructure; and to integrate piecemeal cell lineage data so far obtained into a global and coherent view of the Human Cell Lineage Tree in health and in disease, thus causing a leapfrog advance in biology and medicine.

Impact
The Human Cell Lineage Tree Flagship initiative will drive major innovation in medicine, biology, biochemistry, biotechnology, bioinformatics, computational biology, computer science, and computer systems. The goal of high-throughput and complete characterization of large numbers of individual cells from multiple biochemical and biological aspects will drive all known technologies for single-cell isolation and analysis to the limits and necessitate innovation to go beyond, driving competitiveness of all parties involved. These high-throughput and broad-spectrum single-cell assays will generate very large volumes of data. The need to handle such unprecedented volumes of single-cell data and extract the relevant biological and biomedical knowledge will necessitate bioinformatics and computational biology to generate new algorithms and new computational methods. At the same time, supporting the entry, storage and access of this data, and the computations to be carried out on it, will put to the utmost test the most advanced approaches to large-scale computer systems, storage, and networks.

The ability to place high-quality single-cell information in the context of the Human Cell Lineage Tree would enable a critical advance in biology and medicine, answering many pressing open questions in biology and medicine. Thus, the Human Cell Lineage Tree initiative will promote human health and the quality of life by elucidating the genomic causes of aberrations and thereby reveal new therapeutic avenues for a wide variety of acquired and inherited disorders, such as cancer, diabetes, fertility, neurodegenerative disorders, in compliance with the European Strategy (COM(2002)27 final) which focuses on “Life Sciences and biotechnology”.

Integration



Uncovering the human cell lineage tree would require a unifying approach that relies on a large federated effort of developing and integrating methods from many scientific disciplines, as described in the attached table of Scientific Disciplines and Research Topics, which is also available online (www.weizmann.ac.il/lineage).

The initiative consists of two major efforts: (1) A very broad Science effort in biology and medicine, to apply cell lineage analysis to central open problems in human development, growth, renewal, aging and disease (in particular cancer and inherited disorders), in all organs and systems, giving rise to an ever more coherent and accurate view of the human cell lineage tree, in health and in disease. (2) A large federated multi-disciplinary Technology effort, to build the cell lineage analysis collaborative infrastructure, integrating research and development in biotechnology, computer science, computational biology, bioinformatics, mathematics, statistics, and computer systems. The biotechnology task is to generate data from individual cells, providing accurate genome, transcriptome, proteome, and metabolome profiles of cells at key ramifications of the Human Cell Lineage Tree. The computational and mathematical task is to turn data into knowledge. The computer systems task is to support the entry, storage, access and presentation of data and knowledge. Successfully addressing an ICT challenge of this magnitude requires massive industrial involvement currently exemplified by large-scale companies such as IBM, Microsoft, and Google.

Plausibility
Theoretically, cellular genomic signatures could be gleaned by sequencing the cells' genomes. Prices of whole-genome sequencing are going down rapidly and will soon cross the 1,000 Euro per Human genome. At these prices, reconstructing the entire cell lineage tree of one Human would cost 100,000 trillion Euro. Therefore much more efficient ways of cell lineage reconstruction must be sought.

Fortunately, analyzing even a fraction of the genome of each cell can provide sufficient signal for meaningful lineage reconstruction. The technology challenge is architecting an accurate high-throughput cell lineage analysis infrastructure initially building on available technologies and driving technological development to get maximal signal from each cell at minimal cost and maximal speed.

The plausibility of the proposed approach has been demonstrated by a cell lineage analysis project that started at the Weizmann Institute 7 years ago, and expanded into a national Israeli consortium 4 years ago, to include Hebrew University, Tel Aviv University, Technion, Sheba Medical Center, and Rambam Medical Center. Preliminary results of this work are startling (PLoS Computational Biology 2005, 2008, PLoS One, 2008). We confirmed in mice that cancer indeed starts from a single aberrant cell (Cancer Research 2008), and more recently that leukemia relapse after chemotherapy is initiated by rarely-dividing leukemia stem cells, as illustrated in the figure below (showing leukemia cells sampled from a patient at diagnosis and at relapse after chemotherapy, and leukemia stem cells isolated at diagnosis; manuscript under review). The Human Cell Lineage Tree initiative will expand on this foundation and use complementary approaches for lineage tracing for control and validation.

Organisation



The Human Cell Lineage Tree initiative is organized around of two main efforts and of two secondary efforts: a Science effort and a Technology effort explained above. An Operations effort will operate several regional cell lineage analysis centres serving the Science effort as well as an international data and computing cloud that coalesces the data and supports turning it into knowledge. Management will support the entire operation, also addressing specific ethical and legal questions arising from the new science and technology efforts, as well as pursuing scientific, industrial and public dissemination and educational activities, with a keen eye on the IPR aspects of the project and marketing opportunities.


Join us

If you are interested to join to this research effort, you are welcome to contact the Lineage Flagship Secretariat. You can view the Team and Research Disciplines here.