Systems and synthetic biology approaches to cell division
Cells proliferate by division into similar daughter cells, a process that lies at the heart of cell biology. Extensive research on cell division has led to the identification of the many components and control elements of the molecular machinery underlying cellular division. Here we provide a brief review of prokaryotic and eukaryotic cell division and emphasize how new approaches such as systems and synthetic biology can provide valuable new insight.
KeywordsCell divisionSystems biologyCellular dynamicsBiological networksSynthetic biologyBioengineeringOrigin of life
Cell division: one of life’s key processes
“Any system capable of replication and mutation is alive”, wrote Alexander Oparin in 1961 (Popa 2004). Indeed, replication is one of the central features that defines a living object (Trifonov 2011). Through replication, copies of a living organism are generated. An important principle in biology is that cells replicate by division. Unicellular organisms typically replicate by symmetric division while multi-cellular organisms often replicate by an initial cell fusion followed by development of a multicellular individual through many cycles of cell division, starting from that primary cell.
In eukaryotic cells, the vast majority of the genetic material is located within the membrane-encapsulated nucleus. Next to doubling the genome, cell division involves the distribution and the organization of the chromosomal mass (in a process called mitosis) and the formation of two new nuclei, as well as the distribution of the cytoplasm among the two daughter cells (Fig. 2b–d). Segregation of the chromosomes is conducted by an apparatus called the mitotic spindle which is composed of a large set of proteins. During mitosis, the chromosomes are tightly controlled to evenly segregate so that the resulting daughter cells have the same amount of chromosomes. In exceptional cases (e.g. in the formation of sperms and oocytes), division occurs without chromosome duplication, which leads to the formation of cells with half the amount of chromosomes of the primary cell (in a process called meiosis).
While the above modes of division are the most common, cell division can also occur asymmetrically, leading to the generation of daughter cells with a molecular composition that is different from the mother (Gonczy 2008). Under physiological conditions, asymmetric cell division involves a symmetric division of the genetic material followed by an asymmetric division of the cytosol. Asymmetric division of the genetic material is typically pathologic and occurs in cancer cells.
While cell division—symmetric or asymmetric—typically yields two daughter cells, multi-daughter cell division also occurs in biology, though with low occurrence. For instance, protozoans of the genus Plasmodium commonly undergo division into three or more cells. In engineered environments, multi-daughter divisions can be induced by confinement (Tse et al. 2012). Such daughter cells often suffer from chromosomal abnormalities, so-called aneuploidy. Multi-polar mitosis and aneuploidy are frequently observed in cancer cell divisions (Kops et al. 2005; Vitale et al. 2010). Here the spindle apparatus adopts a multi-polar configuration, in contrast to a typical bi-polar structure. Multi-polar segregation of genetic material may be associated with multipolar cytokinesis, bipolar cytokinesis or no cytokinesis (Gisselsson et al. 2010).
Dissecting cell division
Timeline of key discoveries in cell division
Symmetric chromosomal division
Actomyosin system in cytokinesis
The restriction point
APC and proteolysis
SCF and F-box proteins
In vitro assembly of microtubule aster
Division genes in C. elegans
Self organization of Min surface waves
Reconstitution of contractile FtsZ rings in liposomes
Division genes in humans
In vitro assembly of centromere and kinetochore
Bottom-up reconstruction of cell cortex
New approaches to biology, namely systems biology and synthetic biology, have recently emerged that are also increasingly used to study cell division. The systems biology approach relies on the usage of statistical physics, probability theory and kinetics to understand the structural and dynamical complexity of biology at the full system level. Systems biology integrates large data sets to capture how function is generated from its components. Synthetic biology, on the other hand, involves building and engineering biological or biology-inspired components that are subsequently studied inside or outside of the cell. In this way it aims at developing a range of useful applications as well as at understanding how biological complexity emerges from its components. A common approach in synthetic biology is to build in vitro synthetic systems. Synthetic variants of biological systems provide a great opportunity to decode the constraints imposed by the complexity of natural evolved biological systems. The two approaches provide important complementary information about cell division.
Systems biology approach to cell division
Traditionally, biochemistry and molecular biology examine the properties of the biomolecules in bulk. With single-molecule techniques, biophysicists can now study the properties of even single biomolecules in details. To understand the supramolecular functional properties of living organisms, of which replication is an example, one needs to know, however, not only which molecules are involved and how they function, but also which are the many interactions between them (Jeong et al. 2001; Mashaghi et al. 2004). In the systems approach to biology, properties of biomolecular networks are studied with an emphasis on the dynamics of the molecular networks at the system level.
Another important topic in systems biology of cell division is the connection between the cell cycle and cell growth. For some cell types, the cell size increases to a threshold, beyond which division occurs (Leslie 2011). For other cells, however, there is no critical size but rather a critical growth rate (Son et al. 2012) at which cell division occurs. Furthermore, on rare occasions, cells duplicate their genomes, sometimes even multiple times, without dividing. These cells are called polyploids and are commonly seen in plants, the animal kingdom (Sher et al. 2013) and in human cancers (Storchova et al. 2006). With the development of new technologies (such as microfluidics systems with a mass sensor), precise monitoring of cell size has become possible (Son et al. 2012). Considering the ongoing systems biology research on cell growth (Ferrezuelo et al. 2012) and metabolism (Slavov et al. 2011), a better understanding of the interplay between cell growth and division can be expected in the near future. The systems approach can also be used to address epigenetic factors. Recent evidence, for example, indicates a connection between cell cycle dynamics and circadian rhythm (Kowalska et al. 2013). For example a nuclear protein is found to convey circadian gating to the cell cycle (Kowalska et al. 2013). Importantly the circadian clock is known to govern processes such as sleep, functioning of the gastrointestinal, respiratory and cardiovascular systems (Gachon et al. 2004). The discovery of the circadian gating of the cell cycle thus raises questions about connections between irregular sleep, meal times and health.
Synthetic biology approach to cell division
As one of the fundamental processes of life, cell division is of immediate interest to synthetic biologists. There are many interesting questions: What is the mechanism of cell division? Can engineering the components of the divisome help disentangling this? What are the minimal requirements for a cell to divide? Could we even engineer cellular division from the bottom up? And if so, how can we ensure high fidelity and multiple-cycle continuation in engineered cell division?
With the rapid progress in systems analysis of cell division as well as bottom-up engineering of this process, there is growing confidence for new insights into cell division, yielding hope that this will lead to better therapeutics and improved treatment of human pathologies. Cell division is impaired in many diseases such as cancer, neurodegenative disorders, cardiovascular and rheumatologic pathologies (Zhivotovsky and Orrenius 2010). Drugs targeting cell division, such as those targeting mitotic entry and the mitotic spindle, have been proposed and tested in animal models of cancer with remarkable success. An even better strategy turned out to be targeting mitotic exit and cytokinesis (Manchado et al. 2012; Domenech and Malumbres 2013). So far, none of these strategies have gained clinical success in humans, but the potential of this approach is clear. Cell division inhibitors are also obvious potential antibacterial drugs (Lock and Harry 2008). A number of molecules have recently been designed and successfully used to selectively target FtsZ, leading to division impairment and antibacterial activity (Ruiz-Avila et al. 2013). It is our hope that systems and synthetic biology of cell division will furthermore lead to new cell-cycle based therapeutic strategies for cancers, antibiotics-resistant bacterial infections and other relevant pathologies.
This special issue on cell division provides scientists with an up-to-date selection of papers from internationally leading laboratories that, through their diversity of backgrounds, help to display the interesting complexity and variety of cell division. We hope that this thematic issue will serve as a platform that will provide insight and stimulate further discussion and follow-up research. Finally, we wish to express our sincere gratitude to the authors of the articles in this special issue.
The authors are grateful to Dr. Bertus Beaumont for a critical reading of the article. One if us (C.D.) is supported by the European Research Council ERC Advanced Grant #247072 (NanoForBio).