A Giant Leap for Synthetic Genes

Science magazine has just published the latest tour de force in building genetic machinery from the ground-up since Mycoplasma laboratorium (“Mycoplasma of the laboratory”), dubbed Synthia by some. M. lab, the “synthetic cell,” represented a major milestone in the synthesis of functional DNA, which was announced just four years ago [1]. Craig Venter’s group from the JCVI had reported the complete chemical synthesis of a chromosome that was able to support living, bacterial Mycoplasma genitalium cells.
 
This time in 2014, a different team of scientists synthesized a chromosome that can support living yeast cells [2]. The ultimate goal of the  Synthetic Yeast 2.0 project (http://syntheticyeast.org) is to build the entire genetic make-up of a yeast cell and use it to boot-up Sc2.0. How ambitious is this endeavor? For reference, M. lab is a tiny bacterium that measures about 0.1 micrometer across and carries 0.58 million letters, or nucleotides (A’s, T’s, C’s, and G’s), in its complete genetic code. Sc2.0 will measure a whopping 10 micrometers across (the width of 100 M. labs). The chromosome that the yeast team built, chromosome number 3, consists of 0.27 million letters. All together, the genetic code of Sc2.0 may add up to 14 million letters.
 
This accomplishment has major implications for human cell engineering, and for understanding life. Compared to mycoplasma, the internal organization of yeast cells more closely matches human cells. Furthermore, the yeast team added many unique, synthetic features to the yeast chromosome and demonstrated that this chromosome could still support life. The function of the new features is to aid the process of clipping out portions of the chromosome at specific sites in order to discover what happens to yeast after you eliminate presumably “non-essential” stuff.
 
This demonstration that a huge synthetic chromosome can reside peacefully amongst the other 15 native chromosomes inside a eukaryotic cell is a major milestone for synthetic biology. We (humans) are also eukaryotes. The yeast team’s work is an important step for advancing human cell engineering. The work helps to determine to what extent a eukaryote will tolerate artificial genetic “plug-ins”. Now that the size limit is bigger than ever reported, we can build more complex and more useful synthetic systems. The work will also help us to finally answer the vexing question of whether our “junk” DNA is essential for life, or perhaps just an evolutionary artifact.
 
Very impressive work scientifically, but what moves me the most is the personality of the endeavor. Jef Boeke had organized this effort around an undergraduate lab course called “Build-a-Genome” (or BAG) to give college students an authentic graduate-level research experience [3]. Students were assigned chunks of the synthetic chromosome to build. I can only imagine how amazed they must be to see the impact that the end-product has had on basic research and synthetic biology.
 
The international yeast team includes scientists from Johns Hopkins University, The Carnegie Institution of Washington, New York University, and Loyola University in the USA, Institut Pasteur and Université Pierre et Marie Curie in France, the University of Edinburgh in Scotland, and Pondicherry Biotech in India. One of the leaders of this effort, Jef Boeke, was interviewed on NPR’s Science Friday [4]. Yizhi “Patrick” Cai, who happens to be an alum of the widely popular International Genetically Engineered Machines Competition (iGEM), was recently awarded a grant of 1.8 million pounds to establish the new Edinburgh Genome Foundry.
 
Congratulations team yeast! Only 15 more chromosomes to go…
 
1. Gibson, D. G., Glass, J. I., Lartigue, C., Noskov, V. N., Chuang, R.-Y., Algire, M. A., et al. (2010). Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science, 329(5987), 52–56. doi:10.1126/science.1190719
2. Annaluru, N., Muller, H., Mitchell, L. A., Ramalingam, S., Stracquadanio, G., Richardson, S. M., et al. (2014). Total Synthesis of a Functional Designer Eukaryotic Chromosome. Science. doi:10.1126/science.1249252
3. Teaching synthetic biology, bioinformatics and engineering to undergraduates: the interdisciplinary Build-a-Genome course. (2009). Genetics, 181(1), 13–21. doi:10.1534/genetics.108.096784
4. Engineering Life Through Biology. NPR’s Science Friday, http://www.sciencefriday.com/guests/jef-boeke.html#page/full-width-list/1
 
 
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