The development of the human body from a single cell to many trillions of cells is an exceedingly complex process that depends on precise communication between cells. The process of cell communication results in cell differentiation into multiple types.
Cellular identity is manifested in attributes such as size, shape, and function. Organ shape and function emerges from interactions between cells. Here, each cell could be compared to a “micro-robot” following a specific program. This program is tightly controlled, which is why the left hand is approximately the same size as the right hand. How this is achieved is one of the great mysteries in biology. Another mystery is why some organs are able to significantly regenerate after being damaged and others are not. Understanding the coordination, or communication protocols, between these cellular micro-robots is critical for solving these mysteries.
Cell communication is exceedingly important. A breakdown in cell signaling results in birth defects and diseases that arise later such as cancer, type 2 diabetes, and Alzheimer’s. Recently, tremendous strides have been made to generate small organs or organoids directly from individual patients to study how various diseases occur. For example, brain organoids have been produced and cultured to study how the ZIKA virus infects brain cells 1.
These methods could be considered the early successes for a new field – synthetic developmental biology. Methods to generate human organoids are rapidly maturing and provide hope for testing novel, patient-specific treatments and for creating functional organ replacements that do not face transplant rejection. However, significant challenges arise in making lots of human organoids with tight quality control on the shape, size and biological responses that these organoids produce2. Such protocols produce low yields with highly variable results.
A major effort is required to quantitatively understand how cells interact with each other and their environment to create different kinds of organoids with specific size and shape. Surprisingly and perhaps counter-intuitively studies in non-human systems are both important and effective to seek answers to several key questions:
- How do groups of cells communicate with each other to create three-dimensional shapes with limited external inputs?
- How do chemical signaling and mechanical forces influence outcomes of organ development?
- What determines the size of synthetic organoids generated in the lab and how can this be controlled?
Researchers frequently employ several non-human model systems from worms to flies and zebrafish to provide basic answers to those questions. A prime example is the development of the future wing of the fruit fly (Drosophila). This model system has many well-recognized advantages for studying organ development during the larval (post-embryonic) stages. This includes a short generation time, many genetic tools for controlling levels of proteins in groups of cells, and relatively transparent tissues that can be examined using fluorescent microscopy techniques. Additionally, these micro-organs are approximately the same size as human, lab-grown organoids. Elucidating how to control the size and shape of multi-cellular systems from the micron to millimeter scale could form the building blocks for designing larger organ systems.
Several multi-cellular design principles have emerged from reverse-engineering the fruit fly:
- Organs are organized into spatially distinct compartments. The boundaries between these compartments establish a coordinate system necessary for spatially defining the final architecture of the organ.
- Cells compete with each other during organ development. Unhealthy cells are eliminated, ensuring that the organ is optimally fit.
- Many genes involved with spatially patterning the tissue have been identified and functionally characterized. These genes have counterparts involved with human development.
If the activities of gene products (such as proteins) are analogous to human words, then the interactions between multiple gene products could be thought of as sentences. Understanding how to create “sentences” within a given context is key to understanding how cells “think” and “talk” to each other. Additionally, cells use specific signals such as calcium ions to communicate with neighboring cells. For example, calcium ions can serve as signals that can be observed to communicate across large numbers of cells as a result of changes in the mechanical loading of the organ3,4. This could be analogous to a Twitter tweet or an email to the larger community.
In sum, cell communication, or signal transduction, is a process that occurs at multiple length and time scales to coordinate organ development. Cells receive a diverse range of signals from each other and their environment. They constantly interpret these inputs and respond by regulating their behavior. Disease will result if this process breaks down. For example, tumors arise when cells ignore normal contextual signals to stop growing and dividing. Diabetic ulcers fail to heal because cells stop responding to normal cues from the wound.
Increasingly, systems bioengineers are tackling these complex human health problems. A grand challenge for systems bioengineers working on synthetic development is to create bottom-up approaches that instruct cells to generate tissues. However, this goal requires new tools and knowledge derived from interdisciplinary studies. Further, deriving general principles of organ development requires studies in multiple, complementary organ systems. Understanding the design principles that govern organ development throughout the animal kingdom can drive innovative new applications in the emerging field of synthetic developmental biology.
This perspective and additional supporting references are described in the article Reverse-engineering organogenesis through feedback loops between model systems, recently published in the journal Current Opinion in Biotechnology 5. This work was conducted by Cody Narciso and Jeremiah Zartman from the University of Notre Dame. Funding in the Zartman lab at the University of Notre Dame is supported by grants from the National Science Foundation (CBET-1553826) and the National Institutes of Health (R35GM124935).
- Qian, X., Nguyen, H. N., Jacob, F., Song, H. & Ming, G.-L. Using brain organoids to understand Zika virus-induced microcephaly. Development 144, 952–957 (2017).
- Arora, N. et al. A process engineering approach to increase organoid yield. Development 144, 1128–1136 (2017).
- Brodskiy, P. A. & Zartman, J. J. Calcium as a signal integrator in developing epithelial tissues. Physical biology 15, 051001 (2018).
- Narciso, C. E., Contento, N. M., Storey, T. J., Hoelzle, D. J. & Zartman, J. J. Release of applied mechanical loading stimulates intercellular calcium waves in Drosophila wing discs. Biophysical journal 113, 491–501 (2017).
- Narciso, C. & Zartman, J. Reverse-engineering organogenesis through feedback loops between model systems. Current opinion in biotechnology 52, 1–8 (2018).