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HKU with an international research team revealed a novel principle for forming biological patterns Shed light on the formation of natural biological structures

14 Oct 2011

Why human beings have 5 digits in each limb, whereas cattle and horses have only 2 and 1 respectively? In nature, the formation of patterns and structures from biological cells is often precisely controlled, which allows organisms to grow into different shapes and structures. However, the underlying principles of these pattern formations have always been mysteries. A research team that comprises of researchers from The University of Hong Kong (HKU), Hong Kong Baptist University, University of California in San Diego (UCSD) and University of Marburg in Germany, have employed synthetic biology and quantitative modelling techniques to design and engineered a synthetic genetic circuit, and subsequently determined the underlying scientific principle. The result of this research may help scientists to understand the formation of biological patterns. The research is published in the current issue of the leading international scientific research journal, Science.

According to the research team, this study addresses a fundamental question in biology - "How do living cells arrange themselves to form beautiful and ordered patterns in multi-cellular organisms?" Recently, scientists focus on studying how to grow human organs by stem cells, or how to make use of stem cells to repair damaged organs. However, in what way we can achieve this goal still require a lot of scientific knowledge. Since this study helps scientists to understand the formation of biological patterns, in the long run, the insight provided by this study may be useful for stem cell and regenerative medicine research.

The study

The correct spatiotemporal distribution and positioning of cells is fundamental to the formation of biological structures. This research is dedicated to address this basic problem in biology.

Specifically, the researchers, adopting synthetic biology and quantitative modelling, engineered a dual-module synthetic genetic circuit. Using this synthetic genetic circuit, the researchers controlled the motility of Escherichia coli cells (E. coli) to grow from a spot into a periodical stripe pattern (see the attached figure). Furthermore, the researchers analysed the formation mechanism of the repetitive pattern by constructing a mathematical model. By following the modification suggested by the model, the researchers successfully altered the number of stripes present in the pattern. The result of this research provides insight and a new way of thinking to understand the quantitative control of cell's structure formation in the development process.

Research results and significances

The development from a single cell into a full size organism is a complex yet organized process. The process involves cells differentiating into different cell types as well as the coordination of cells in the spatial and temporal dimension in forming orderly structures. In recent years, great progress has been made on the former with the advancements in stem cells reprogramming, yet, little is understood on the latter due to the underlying complexity in biological systems.

This research created a periodic pattern composed of genetically modifying bacterial cells in a spatiotemporal organised manner. Furthermore, the generated pattern is predictable and modifiable. The research result reminds us that, in nature, repetitive patterns and structures are often precisely controlled. For example, human beings have 5 digits in each limb, whereas cattle and horses have 2 and 1 digit(s) in their limbs respectively; the spinal column of human beings is composed of 33 vertebrae, whereas snakes can have over 300 vertebrae. These precisely controlled periodic structures occur frequently in nature, yet the mechanism and the underlying principle of their formation are largely not understood. Therefore, it is difficult to create repetitive structure and to control their number of repeats through genetic engineering. This research is able to easily alter the number of stripes formed by the engineered bacteria, which may help scientists to understand the formation mechanism of different-numbered biological features in different organisms, and may provide a new way of thinking to control their formations.

This is an interdisciplinary research that combines systems biology, quantitative biology, synthetic biology, and physics. The research results not only contribute to understanding the formation of periodic patterns in nature and how we may possibly control them, but also demonstrate the combination of synthetic biology and quantitative biology in the exploration of basic biological principles.

The research team

This research is the collaborative effort of researchers from four universities. Dr. LIU Chen-li of Department of Biochemistry and PhD candidate Mr. FU Xiong-fei of Department of Physics of HKU are the main researchers. Dr. HUANG Jian-Dong and Dr. HUANG Wei of HKU Department of Biochemistry and Professor Terence HWA of UCSD led the biological experiments. Dr. CUI Xiao-dong's group of HKU Department of Physics together with Dr. HUANG Wei developed the optical systems for performing the experiment. Professor Terence HWA of UCSD, Professor Peter LENZ of the University of Marbury, Professor TANG Lei-han of HKBU, and Professor CHEN Guang-hua of HKU Department of Chemistry led the modelling analysis. 

Key researchers from The University of Hong Kong: (from left) Dr. HUANG Wei, Research Assistant Professor, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine and Department of Physics, Faculty of Science, HKU; FU Xiong-fei, PhD candidate, Department of Physics, Faculty of Science, HKU; Dr. HUANG Jian-dong, Associate Professor, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine; Dr. LIU Chen-li, Post-doctoral Fellow, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine; and Professor CHEN Guan-hua, Professor and Head of Department of Chemistry, Faculty of Science, HKU	HKU research team: (Front row from left) Dr. HUANG Wei (Research Assistant Professor, Department of Biochemistry, Li Ka Shing Faculty of Medicine and Department of Physics, Faculty of Science, HKU), Dr. HUANG Jian-dong (Associate Professor, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine), Professor CHEN Guan-hua (Professor and Head of Department of Chemistry, Faculty of Science, HKU) ; (Back row from left) ZENG Hua-ling, FU Xiong-fei, LI Si-hong, (PhD student, Department of Physics, Faculty of Science, HKU) Dr. LIU Chen-li (Post-doctoral Fellow, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine), CHOW Kwan-long (Graduand of Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine) and LIU Li-zhong (Research Assistant of Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine)
Dr. HUANG Jian-dong, Associate Professor, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine, observes the experiment result.	Dr. LIU Chen-li, Post-doctoral Fellow, Department of Biochemistry, HKU Li Ka Shing Faculty of Medicine, records the growing process of E. coli by taking photos
A special growing pattern of biochemical engineered E. coli.	Synthetic genetic circuit can control the number of rings that E. coli forms.