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Dr Musa Mhlanga |
South Africa intends to achieve international recognition in synthetic biology within the next five years by establishing a synthetic biology emerging research area at the CSIR. This initiative is supported by the Department of Science and Technology and other partners. The synthetic biology research area will consolidate current expertise and create new scientific research and development capabilities that will be applicable broadly in health and industry, thus having social and economic benefits for South Africa.
Dr Musa Mhlanga was recently appointed competency area manager of synthetic biology and research group leader of the gene expression and biophysics group at the CSIR. An American-born cell biologist, he holds a PhD in cell biology and molecular genetics from New York University School of Medicine. He began his PhD at the Rockefeller University in the laboratory of David Ho where he worked on spectral genotyping of human alleles. He then went on to work on the development of in vitro and in vivo applications of molecular beacons for their use in visualising RNA in living cells with Fred Russell Kramer and Sanjay Tyagi. Upon completion of his doctoral work he was awarded a National Science Foundation postdoctoral fellowship to work at the Institut Pasteur in Paris in the laboratory of nuclear cell biology. There he worked on the imaging of gene expression, RNA transport and single molecule visualisation and tracking of RNA in living cells.
To build the necessary research infrastructure at the CSIR for this area, Mhlanga says that multidisciplinary postdoctoral fellows and students are needed, especially people with backgrounds in cell biology, genetics, microbiology, physics, mathematics and engineering.
Engineers view biology as a technology. Synthetic biology includes the broad redefinition and expansion of biotechnology, with the ultimate goals of being able to design and build engineered biological systems that process information, manipulate chemicals, fabricate materials and structures, produce energy, provide food and maintain and enhance human health and our environment. Biologists are interested in learning how natural living systems work. "One simple, direct way to test our current understanding of a natural living system is to build a version of the system in accordance with the understanding of the system," Mhlanga explains.
There are several key enabling technologies that are critical to the growth of synthetic biology. These are sequencing and high-throughput technologies, fabrication, mathematical and physical modelling, and measurement and quantification.
In the biological sciences, says Mhlanga, "we have reached a point where we have acquired a tremendous amount of information about the natural world through what is generally known as the 'omics' technologies, such as genomics, kinomics and proteomics. The term 'omics' refers to the comprehensive analysis of biological systems. A variety of 'omics' sub-disciplines have begun to emerge, each with its own set of instruments, techniques and software. The 'omics' technology that has driven these new areas of research consists of DNA and protein microarrays, mass spectrometry and a number of other instruments that enable high-throughput analyses. This information is basically descriptive of nature at the molecular level, and informs us, for example, about a specific gene and its sequence, or that a specific protein from a particular gene is expressed in certain biological contexts."
The challenge is to take this huge amount of information and try to decipher how living organisms have evolved to use molecular pathways in beneficial ways in their environments. This may be a single gene or a set of genes with a specific activity in a bacterium that enables it to survive in extremely cold or extremely hot conditions. Understanding how this works at the molecular level enables scientists to model and construct new systems. The next step is to take that understanding and make an organism or a system with the desired properties, such as one with cold or heat-resistant properties.
He says a number of approaches must be pursued in synthetic biology to model these systems so that we can understand them. For example, an engineer might use wind tunnel modelling to understand how birds fly. The knowledge that we have gained from the modelling of systems is then used to fabricate devices or pathways. Since all of this occurs at the molecular scale, it is necessary to observe and measure events in living cells at the molecular scale. When what is being modelled or designed is gene expression or a specific genetic pathway, measuring what happens in real time requires an engineer's knowledge of the molecular activities surrounding gene expression.
Three areas are therefore encompassed in synthetic biology: synthesis, design and characterisation. We need to measure and understand the system, model the system, and if we wish to recreate or tweak the system, we need to be able to observe and manipulate events in real time.
What does this mean in concrete terms for those working on synthetic biology at the CSIR?
Mhlanga explains that one of the groups working on biomaterials is attempting to combine various materials from nature and organic chemistry to make specialised surfaces on which beneficial enzymatic reactions can occur. Another group is investigating how plants capture light energy and ways to recreate the chlorophyll arrays of plants and then harness the energy in the same way as plants do.
The gene expression and biophysics group is concerned with understanding and engineering gene expression. All life on earth depends on genes, and the group's interest is in engineering the response and activation of genes in all kinds of situations - whether they are in artificial bacteria, or whether they are in living cells. "If we can engineer the transcription of the genetic response in a diseased state, then we can tweak the gene expression response either to protect the organism or to assist the organism to fight infection. To do that, we work on eukaryotic cells and on the nucleus where DNA is stored (in eukaryotic cells)," he adds. What they try to visualise at the single-molecule level is the actual process of transcription - how the machinery that converts DNA to protein through RNA is assembled and how this machinery can be engineered to choose or activate one gene or one piece of DNA as opposed to another, and to make one RNA as opposed to another RNA.
An important project is to obtain super-resolution of biological objects. That means being able to see the actual working parts of biology (DNA, RNA and protein) which are below 60 nm in size. For this purpose a super-resolution microscope is being built to observe nano-scale objects, beyond Abbe's limit (~250 nm). Most of the events occur at the nano scale, so they need to be able to resolve objects smaller than 250 nm, down to 30 nm or less. Two approaches are used to achieve super-resolution, one called photo-activated light microscopy (PALM), and a second called stochastic optical reconstruction microscopy (STORM). Both involve deconvolving and engineering point spread functions of light. This type of microscopy relies on advanced image processing, computing power and advanced optics. The microscope, which will use the supercomputer cluster on the CSIR campus for data analysis, is scheduled for completion by the end of August this year. This laboratory at the CSIR will be one of the few in the world with the equipment to observe nano-scale objects. There are only a few organisations worldwide that are equipped for this type of microscopy, such as Harvard University, the National Institutes of Health, US, the Pasteur Institute in France and the Max Planck Institute in Germany.
The second phase of this project will be to build a high throughput visual screening platform to hunt for small molecules that can be effective against the major infectious diseases in South Africa and the rest of Africa.
Enquiries: CSIR Communications
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