Minimum Viable Cell

JCV3.0Craig Venter is on a quest to find the Minimum Viable Organism—a.k.a. minimal bacterial genome. It seems the task is 70% complete now.

Cells are the fundamental units of life. The genome sequence of a cell may be thought of as its operating system. It carries the code that specifies all of the genetic functions of the cell. Understanding the molecular and biological function of every gene in a cell, and building a minimal genome that includes only genes essential for life, are key goals of today’s biology. A minimal cell is usually defined as a cell in which all genes are essential.

DNA sequencing is a lot like reading the code of life, and the quest for a minimal genome is akin to defining the algorithmic complexity of life. Since the first genome sequences, there has been much work to identify nonessential genes and define core sets of genetic functions. However, as appealing as it may sound, a minimal cell is far from a well-defined goal, and faces both technical and perhaps other more philosophical hurdles related to the proper concept of life.

Often, more than one gene can perform a particular essential function, meaning neither gene would be essential. On the other hand, the genetic requirements for survival, and therefore the minimal genome, depend on the environment in which a cell is grown. To survive in nature, most bacterial cells must be capable of adapting to different environments. Typical well-known bacteria such as Escherichia coli carry 4,000 to 5,000 genes. They are highly adaptable, because many of their genes provide functions that are needed only under certain growth conditions.

In 1984, mycoplasmas were proposed as models for understanding the basic principles of life. The mycoplasmas typically grow in the nutrient-rich environment of animal hosts, and have the smallest known genomes of any autonomously replicating cells.

In 1995, the first mycoplasma genome was sequenced. With 525 genes, Mycoplasma genitalium has the smallest genome known for an autonomously replicating cell found in nature. Yet it contains many genes that are nonessential for growth in the laboratory. A comparison of M. genitalium with other known genome sequence, Haemophilus influenzae —1815 genes—revealed a common core of only 256 genes, much smaller than either genome. This was proposed to be the minimal gene set for life.

Craig Venter and his team set out to find a minimal cellular genome experimentally by designing and building one, and then testing it for viability. Their goal has been a cell so simple that they can determine the molecular and biological function of every gene. When the first hypothetical minimal genome was assembled, it proved nonviable, and convinced them that they did not have sufficient knowledge to design a functional minimal genome from first principles.

On May 21, 2010, Science reported the complete chemical synthesis and installation of the genome of M. mycoides JCVI-syn1.0. M. mycoides is a bacterial species which grows much faster and allows quicker experiments than M. genitalium. This genome was an almost exact copy of the wild-type M. mycoides genome, with the addition of a few much publicized watermarks, including an html script including an email link, several lists of authors, and quotes from three of them:

  • James Joyce, “To live to err, to fall, to triumph, to recreate life out of life”
  • Robert Oppenheimer (uncredited): “See things not as they are, but as they might be”
  • Richard Feynman “What I cannot build, I cannot understand”

Now the J. Craig Venter Institute (JCVI) and Synthetic Genomics, Inc. (SGI) report the design and construction of a new cell, JCVI-syn3.0(1), which is a new working approximation to a minimal cell. Its genome is substantially smaller than that of M. genitalium—473—genes, and its doubling rate is about five times as fast—~180 min. Very interestingly, in syn3.0, 149 genes cannot be assigned a specific biological function.

We still don’t understand 30% of the minimum viable organism that we are able to build today, which means that, although we cannot understand what we cannot build, we need not necessarily understand what we can build.

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(1) Hutchison, C., Chuang, R., Noskov, V., Assad-Garcia, N., Deerinck, T., Ellisman, M., Gill, J., Kannan, K., Karas, B., Ma, L., Pelletier, J., Qi, Z., Richter, R., Strychalski, E., Sun, L., Suzuki, Y., Tsvetanova, B., Wise, K., Smith, H., Glass, J., Merryman, C., Gibson, D., & Venter, J. (2016). Design and synthesis of a minimal bacterial genome Science, 351 (6280) DOI: 10.1126/science.aad6253

Featured Image: Fig 5 op.cit.

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