UNDERSTANDING OF CELL BIOLOGY BY CREATING A CELL ATLAS REQUIRES COLLABORATION
By Dr. Duangqing Pei, and David Beier
Recently, philanthropists Priscilla Chan and Mark Zuckerberg announced their bold new institute, the Chan Zuckerberg Initiative (or CZI), funded with up to $3 Billion and whose goal is to help cure, manage, or prevent all disease by 2100. They deserve particular praise and attention, because they have wisely chosen their initial targets: a cell atlas and new work on infectious disease. Here, we discuss the wisdom of selecting cell atlas as a driver to better understand biology and lay the foundation for application in medicine. In our view, this approach has three benefits. First, it creates a unique opportunity for international scientific cooperation. Second, it fosters convergence of disciplines such as biology, computer science and data analytics, genomics, physics and chemistry. Third, it will result in new applications of cell therapy.
The desire and decision to map the cell landscape in humans through the cell atlas project is not per se new1. However, it is a timely and highly relevant effort. We wholeheartedly welcome this initiative to be conducted initially in California. California is home to the State-sponsored Center for Regenerative Medicine (CRM), prominent universities (University of California San Francisco, Stanford, UC Berkeley), and venture capital firms focused on stem cell biology, regenerative medicine, genomics and gene editing. However, unlike successes in protein and antibody therapies pioneered in that state, stem cell therapy has been much harder than initially imagined due to the inherent complex of cell identity, function and plasticity. The human body is estimated to have 60 to 200 trillion cells derived from a single cell, the fertilized egg. Differentiated cell types of the major 300 classes include the following: different types of skin cells, immune cells, brain cells, and muscle cells. Cell is a unit that genes, proteins and their complexes work in harmony to fulfill specific function the body needed. Therefore, a deeper understanding of our cells is vital to its application as an instrument of therapy for many degenerative diseases.
Scientifically, two inter-related questions must be answered for a basic understanding of cells. First, how does one cell give rise to other cells? The answer to this question will ultimately provide a lineage map of cell fate from the first cell, i.e., the fertilized egg, to all cells in body. This knowledge will be essential for us to understand disease process ranging from cancer to autoimmunity. We can also leverage the deep knowledge of cell fate to create any cell we needed both in vitro and in vivo. The second question is how many diverse or distinct cell types can we classify from all of our cells? The answer will provide a comprehensive cell landscape that can help locate exactly where individual cells are. This landscape will include a catalogue of cell locations, cell types, the statuses of the cell, and the lineage and the progression of a cell from its original status to its operational stage. With the lineage and landscape map in hand, one can not only better understand diseases, especially those degenerative diseases in which cells simply give up, but also provide a rationale for cell replacement therapy with precision.
Ultimately, the dynamic lineage map and the cell landscape should provide us with the necessary knowledge of our lives. Critically, like the international consortium who worked together on the Human Genome Project more than twenty years ago, a coordinated international effort for the creation of a comprehensive cell atlas should go global. It is through robust cross-border cooperation that such a project can leverage the expertise and resources from both private and public sectors to ensure a speedy execution. Dividing up the duties among parties, teams and countries interested in this complex multidisciplinary effort can much more efficiently accomplish the tasks which need to be undertaken. In addition, even the massive effort like the one undertaken by the Chan Zuckerberg Initiative (CZI) would be insufficient if it is just one group that is funding this effort. Focusing on pooling resources across jurisdictions and funding sources will ensure its success. Lastly, a broad international effort will be necessary due to the biological reality that the global knowledge and insights gained from the differences in the dimensions of populations in different continents should enrich the project.
Scientifically, the initiation of a project of this scale requires input from scientists across a large spectrum of disciplines, including drug development, stem cells, regenerative biology, bioinformatics, and genetics. Compared to the technologies of just a few years ago, stunning advances have been made in areas such as single cell genomics, computational biology, data visualization, and analytics. All of these advances will permit a far more sophisticated and rapid execution of a cell atlas. In a recent two-year time period, the number of cells that could be analyzed in a relevant period of time leapt from 18 cells to 100,000 cells. The scale, speed and cost of two and three-dimensional analysis have been accelerating well beyond the increase in computing power rule of thumb known as Moore’s law.
Our understanding of cell and cell fate has undergone a dramatic revolution. Just now, skin fibroblasts or other somatic cells such as cells from human urine sample from a 90-year-old individual can be reverted back in time approximately 4–5 days after fertilization for the egg of that particular individual. This technological advancement is incredibly significant, as now one can have a complete life history of a 90-year-old individual and his or her embryonic cells can be analyzed for answers to his or her life’s questions through focusing on the individual’s health problems. Going forward, the modern optical microscope (first advanced by Zacharias Janssen around the 1590s) will be supplanted by the genomic sequencer.
These new capabilities in many areas of science have ushered in a new era in which human biology can be investigated with such accuracy that health and illness may become demystified. Moreover, the heterogeneity in disease will become more evident. Securing the benefits from such promises can only be achieved through convergence of current and future technologies in biology, medicine, chemistry, engineering, IT, material sciences, and mathematics. Like the Apollo mission to the moon, this convergence will provide a fertile ground for new science, new engineering, and new ideas, all of which will benefit mankind in new ways that we can only imagine.
Finally, a cell atlas will fill a huge knowledge gap about ourselves. Each one of us is very different, even from our closest relatives. While the genomes between two family members have only differences of a few percentages, differences in appearance and intellect can be vastly different due to differences between the cells, tissues and organs, and epigenetics. By mapping all cells and their lineages, one may be able to understand both the functional and structural differences among our cells and, ultimately, the uniqueness of our individual selves.
One possible outcome of a fleshed-out cell atlas could be that armed with the knowledge of our cell compositions, a doctor may be able to diagnose any abnormalities with pinpoint accuracy. It may ultimately be possible that an illness–a synthesis of abnormalities at the level of cells and tissues — can be “seen” in all of its fourth dimensional beauty by health providers.
One motivation for a cell atlas is to give scientists the ability to define a cell in vivo so that cells generated in vitro are functionally equivalent. Therefore, the cells generated in vitro can be transplanted back to the patient in a place and a time to restore the original function. An appropriate analogy this development would be repairing a car with OEM parts.
Compared to our understanding of the universe, we are dwarfed in the understanding of our bodies. By employing known technologies, we should make a bold attempt to map all human cells and lineages. Just as President John Kennedy once challenged the American people to land a man on the moon or as Chinese leaders have recently committed their nation to the new frontiers of life science4, the international scientific community should dare to be great by being bold. Together, we can achieve much and advance the human condition.
Dr. Pei is a Professor of stem cell biology and also serves as the Director General (President) at the Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, in Guangzhou, China.
David Beier is Managing Director of the San Francisco based life science venture capital firm Bay City Capital and was previously Chief Domestic Policy Advisor to Vice President Al Gore and served for many years as a senior executive of Amgen and before that Genentech.
1 Source: For example, Dr. Pei recommended that the scientific community should map both the lineage and the landscape. He presented this idea in a proposal in 2007 — which called for a project named the Cell Lineage and Atlas Project (CLAP) in the 313rd Xiangshan Meeting, a think-tank type series organized by — the Chinese Ministry of Science and Technology (MOST), Chinese Academy of Sciences and Natural Science Foundation of China.
2 Source: Regev, Avid. “The Human Cell Atlas. “Department of Biology at MIT. Presentation at Howard Hughes Institute (2014). Link available at https://www.genome.gov/multimedia/slides/gspfuture2014/10_regev.pdf
3 Source: Simonite, Tom. “Moore’s Law is Dead. Now What?” MIT Technology Review (May 13, 2016). Link available at https://www.technologyreview.com/s/601441/moores-law-is-dead-now-what/
Moore’s Law refers to an observation made by Gordon Moore, the Intel co-founder, in 1965. He observed that the number of transistors per square inch on integrated circuits had doubled every year since their invention. Moore’s law states that this trend will continue into the foreseeable future. The number of transistors per square inch has since doubled about every 18 months. Experts believe that Moore’s law is unlikely to continue indefinitely due to its suggested exponential growth.
4 Source: The Chinese government has announced earlier in 2016 that it would invest up to $9 billion in precision health. According to the McKinsey Global Institute, R&D funding in China has grown at a 27% CAGR the last five years and is expected to reach $20–30B by 2025.