October 23, 2020, by Brigitte Nerlich
Minimal genomes, maximal assumptions
This is another guest post by Massimiliano Simons who is a postdoctoral researcher at the department of philosophy and moral sciences at Ghent University. He is also a member of the Working Group on Philosophy of Technology (WGPT) at KU Leuven, Belgium.
Ten years ago the J. Craig Venter Institute announced the birth of ‘synthia’, the “first synthetic bacterial cell”. This announcement made the headlines of most international newspapers. But soon strong criticisms followed: this was not real synthetic life. For instance, not the whole cell was synthesized, but only the genome, the DNA of the organism.
However, the fact that only the genome was synthesized and inserted in a host cell was not that surprising, once you realize that Craig Venter situated his work in a longer tradition: the search for the minimal genome. My recent article attempts to map the origins and assumptions of that tradition. What especially fascinated me was their systematic use of ‘minimality’ and ‘essentialism’, as in the minimal genomes with only the essential genes for life. I found this remarkable, since these notions are quite heavyweight and one could even say philosophical.
Minimal life in the Cold War
Minimal genome research started with Harold J. Morowitz in the 1950s. His search for minimal life was a product of the Cold War. The Russians were beating the Americans in Space, but also astrobiology became a frontier: if we go to space, will we not encounter alien life forms? How will we detect them? How do they relate to life on Earth?
With biologists such as Aleksandr Oparin among their ranks, the Soviet Union was a world leader concerning these questions. In response the United States started to fund their own biologists. Stanley Miller and his famous experiments on the origins of life is one famous example, but Morowitz is another.
Morowitz believed that the simplest form of life on Earth would also be the most foundational and original one. Were we to find the simplest form of life, we would find life in its purity, stripped of all redundancies and contingencies. It would be life with only the necessary characteristics required to do what it does best: to live, survive and reproduce.
For Morowitz this was an empirical question: minimal life is still around, we just have to find it. But, he did not plan expeditions to the Amazon nor went deep diving in the oceans. Instead, Morowitz used the mail. He sent letters to microbiologists around the world and consulted reference works in biology, scanning for terms such as parvulus (Latin for ‘tiny’).
The candidate that came out of this became famous: mycoplasmas. Mycoplasmas have had a turbulent history of their own (which I describe more fully in the article). Are mycoplasmas really the original, simple, foundational form of life? Morowitz believed so, although he started soon to describe them in terms of minimal genomes. Why? Because in the 1960s molecular biology changed the theoretical landscape: life is DNA and DNA is universal. The foundation of life is to be found, not in the smallest form of life, but in the smallest number of genes. Surprisingly, the genome of mycoplasma is extremely small as well.
However, soon doubts arose whether mycoplasma’s were really the simplest lifeforms. Mycoplasmas are parasites and their genome indicated that they are a product of degeneration: they used to have more genes, but they lost most of them. Why? Because these genes were not required in their parasitic contexts in which they thrived. They ‘outsourced’ genes to the hosts they live in.
Minimal genomes as theoretical entities
New attempts in the 1990s to find the minimal genome abandoned the idea that it was something that one could encounter in the world. Instead it was a theoretical abstraction. How then to find the minimal genome? In 1995 Mitsuhiro Itaya tried to find it through statistical extrapolation: knock out a sample of genes, see which genes are necessary to survive, and generalize this ratio to the whole genome.
But a more influential approach came into being at the end of the 1990s: comparative genomics. Because for the first time whole genomes were sequenced, genomes of different organisms could be compared. The genes which are shared, despite divergent evolutionary paths, would make up the minimal genome. However, this approach raised problems: is it possible that different genes play the same necessary genetic function? The same gene would then not show up in all genomes. And what if not one, but multiple genes fulfilled a function? Individually, they look redundant, but knocking them out together is lethal. Finally, there was the problem of the environment: a minimal genome never stands on its own, but is always relational to an environment for which it is minimal.
Craig Venter and synthetic genomics
This is the context in which Craig Venter joined the research project. Their group, however, advocated a new approach: proof by synthesis. One could only be sure that a genome is minimal by synthesizing it and to see whether the cell would actually survive. This is what, through a number of papers, let to the famous 2010 paper, where they synthesized and transplanted a mycoplasma genome (though they hardly changed anything in the genome). Later papers removed more genes, in search for the true minimal genome.
Within their papers there is a certain shift in motivation, characteristic for the new field of synthetic biology. Though the theoretical motivation stayed, another justification became central: practical biotechnological applications. Minimal genomes could be platform technologies, a chassis for all kinds of biotech applications. The dream was that one could simply insert the desired genes in the synthesized genome and ‘load’ it into the cell, as synthetic biologists typically frame it (often using the software/hardware metaphor).
However, one problem remains: the environment. For which environment was this the minimal genome? Typically the implicit answer is the laboratory environment, either confused with the absence of an environment or deemed a neutral environment. In that sense, there are in fact two ways to understand these sets of essential genes of minimal genomes: essential for any life whatsoever, regardless of environment; but in practice often essential for specific artificial, laboratory settings, where they can perform desires biotechnological operations.
Synthetic biology as technoscience
What should we do with this ambiguity? Should we say that these synthetic biologists are philosophically naïve? That they fail to understand the relational dimension of biology, locked up in their essentialist and atomic view of life? Or, as I try to show in my article, maybe this naiveté is rather a productive element of our current way of doing science, sometimes labelled as technoscience.
The label ‘technoscience’ is often used to stress the interrelations between science and technology. However, some scholars reserve it for a more specific use, namely for a specific type of scientific disciplines that came into being at the end of the 20th century. Technoscience would then refer to scientific disciplines who are focused, not so much on studying actualities, but possibilities.
Nanotechnology is interested not in existing materials, but in exploring the properties of new materials; robotics is interested in what artificial bodies can do, not what they do now. Similarly, synthetic biology might be more preoccupied with how life could be, rather than how terrestrial life actually is. The ambiguity between theoretical universality and biotechnological standardization is crucial for this technoscientific endeavor: one simultaneously explores theoretical possibilities and biotechnological applications, seemingly pleasing both the desire for more fundamental knowledge and the demand for practical applications.