A revisionist history of synthetic biology

Synthetic biology did not start in the year 2000.

1. A lot of important people think that synthetic biology started in the year 2000.

Tim Gardner wrote recently that “synthetic biology began in January 2000 with the side-by-side publication of two articles,” one of which was by Gardner et al. I loved Tim’s 2000 article when it came out, and as a naive 1st year graduate student, I even touted it to my own future Ph.D. advisor as the type of work I wanted to do. But neither it nor its companion article by Mike Elowitz started synthetic biology.

Tim Gardner isn’t alone in attributing the birth (asynbiogenesis?) of synthetic biology to 2000. Jim Collins was a bit more circumspect but he essentially acknowledged the start of the field as being in 2000 or so when he said recently that, “we’re at the very early stages….twelve years is not a long time.”

2. Synthetic biology was happening in 1970.
Har Gobind Khorana and his co-workers were synthesizing functional genes back in 1970,
30 years before the supposed start of synthetic biology. To use Tim Gardner’s words, this experiment also “illustrated the principle that designing biological systems was feasible and reasonably predictable.” What could be more predictable than synthesizing a nucleotide and knowing that a functional protein would come out?

3. Synthetic biology was happening in 1977 (and earlier). In 1977, Bruce Levin and others created — synthesized — an artifical biological system and sought to describe it quantitatively. Rather than limiting their focus to the inner molecular workings of just a single organism, their focus was on an entire ecosystem. In fact they weren’t the first to synthesize artificial ecosystems, they were just some of the most successful. Professor Levin’s team grew to include Richard Lenski, and in 1985 the two penned a very thorough, model-based look at a synthetic ecological system, this time including explicitly “a little genetics”. Back in 1972, Tsuchiya and Fredrickson were predicting, modeling, and successfully observing oscillations in a constructed biological system.

4. Synthetic biology was happening in 1983. One thing that Gardner, Collins, and Elowitz and all the rest infused into their work was a quantitative sophistication about cellular function. The analytical framework they used to understand their biological designs was based on differential equations. Essentially these were mass action models of mRNA and protein synthesis, as regulated by various DNA binding proteins, small molecule inducers, and other factors. The 2000 papers pointed out very successfully that these types of models can be useful in not only understanding, but also designing biological systems. But they weren’t the first examples of quantitative thinkers using mass-action models to predict the behavior of complex networks of interacting biomolecules.

To take just one example, in 1983 and 1984, some seminal papers by Sun Bok Lee and James E. Bailey appeared. They are some of the first examples of a “genetically structured model”, in which the genes, transcripts, and proteins that comprise a functional gene networks are modeled using differential equations, exactly as was done in the 2000 papers. These models from the 1980s predicted the behavior of artificially constructed (or “mutant”, to use the parlance of the times) systems as well as wild-type organisms, too. In one of many lectures given by Bailey looking back over his many career accomplishments, he wrote in 1998:

Any model is more credible if it can also describe, in a consistent fashion, situations different from the one on
which the original model is based. Lee further demonstrated the value of the hypotheses depicted in Figure 3 by showing the capability of the resulting model to simulate both the number of plasmids per cell and the quantity of a key regulatory protein called the cro repressor for a number of mutant plasmids. However, in this respect, Lee went considerably further conceptually and methodologically and established a precedent for a key idea which will undoubtedly become widely embraced in the future. Lee coined the term “genetically structured model” for this concept.”

5. I concede to one grounds for claiming that synthetic biology started in 2000. Before 2000, nearly no one called themselves “synthetic biologists”. If we define “synthetic biology” as whatever self-styled “synthetic biologists” do, perhaps a case can be made for synthetic biology starting in 2000. Of course, this is a circular way to define synthetic biology. Isaac Newton didn’t call himself a physicist. No one did at the time. (Perhaps Newton thought of himself as a natural philosopher.) The OED’s first attested use of the word in its modern sense is from 1840, 113 years after Newton’s death. Yet even though Newton didn’t consider himself a physicist, nearly every physicist alive today would count Newton as one of the greatest physicists ever. Similarly, if synthetic biology is to be a field of research, and not just a club of researchers, we must recognize and strive to build upon the seminal contributions of past scientists, even if they used a different nomenclature. Har Gobind Khorana, James Bailey, and Bruce Levin — to name just a few — were great synthetic biologists — and it can only serve the field to recognize their contributions.

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