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LETTERS TO THE EDITORS

The Smallest Cell

To the Editors:

In the January–February Computing Science column “Imitation of Life,” Brian Hayes asks “Can a computer program reproduce everything that happens inside a living cell?” He begins with a reference to my search some 30 and more years ago for the smallest and simplest living organism. A bit of historical marginalia about that search might illuminate the question and suggest a new plan. Hayes notes that our search took us to the Mycoplasma, then the smallest free-living cells. The search for smallness and simplicity was motivated principally by an interest in the origin of cellular life.

Years later, after the modern reformulation of phylogeny from ribosomal RNA sequences by Carl Woese and his associates, it has become clear that Mycoplasma are not primitive but instead descendants of soil-dwelling proteobacteria, quite possibly the Bacillus, which evolved into parasites. In becoming obligate parasites, the organisms were able to discard almost all biosynthetic capacity by a strategy of gaining biochemical intermediates from the host or from the growth medium in the case of laboratory culture. Most very small Mycoplasma have extremely complicated growth media requirements, so the Hayes question should perhaps ask the computer program to operate in a milieu that must itself be properly and precisely defined. To be adequate, the computer program must include the parameters of the milieu exterieur and their entry as well as the milieu interieur.

Therefore, as I have previously noted and apologized (see references), we had erred in the choice of Mycoplasma for the questions of origins. It is likely that the long evolutionary trajectory of Mycoplasma went from a reductive autotroph to oxidative heterotroph to a cell-wall–defective degenerate parasite. This evolutionary trajectory assumes the simplicity to complexity route of biogenesis, a point of view that is not universally accepted. To pursue this line of reasoning experimentally, we have had to define true autotrophy in a somewhat more precise way than is usually done. This definition depends on carbon dioxide being the sole source of carbon. A number of such taxa have been studied and characterized in considerable detail by full genome sequencing as well as metabolic studies. Hydrogenebacter and Aquifex are examples of such genera. Currently studied species of this type of organism have genome sizes about two to three times that of Mycoplasma genetalium. This is perhaps not so surprising given that the present-day reductive autotrophs come from environments where they are in competition with various other taxa, an activity requiring additional molecular apparatus.

The previous line of reasoning suggests an experimental approach to an organism suitable for the analysis of M. W. Covert and his associates but not obscured by unknown features of a complex and not wholly defined growth medium. To find the smallest, simplest species, the organism of interest must be cultured on a precisely defined minimal growth medium and subjected to an extended protocol of gene deletion. As one continues these knockout experiments one can carry out the Whole Cell computer program in parallel with the knockout program to focus on a complete theory. This all seems to be within the range of the possible. Thank you, Brian Hayes, for finding and noting my ideas of 30 years ago. I would like to suggest that the program being proposed here can be completed in considerably less than 30 years and may finally test the completeness of molecular biology.

Morowitz, H. J. 1984. The completeness of molecular biology. Israel Journal of Medical Sciences 20:750–753.
Morowitz, H. J. 2011. When PPLO became Mycoplasma. American Scientist 99:102–104.
Srinivassan,V., H. J. Morowitz and H. Huber. 2012. What is an autotroph? Archives of Microbiology 194:135–140.
Woese, C. R., and G. E. Fox. 1977. Phylogenetic structure of the prokaryotic domain: The primary kingdoms. Proceedings of the National Academy of Sciences of the U.S.A. 74:5088–5090

Harold J. Morowitz
Robinson Professor of Biology and Natural Philosophy
George Mason University


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