Chapter 5. The Second Coming of Synthetic Biology
"I must tell you that I can prepare urea without requiring a kidney of an animal, either man or dog.” With these words, in 1828 Friedrich Wohler announced he had irreversibly changed the world. In a letter to his former teacher Joens Jacob Berzelius, Wohler wrote that he had witnessed, “The great tragedy of science, the slaying of a beautiful hypothesis by an ugly fact.” The beautiful idea to which he referred was vitalism, the notion that organic matter, exemplified in this case by urea, was animated and created by a vital force and that it could not be synthesized from inorganic components. The ugly fact was a dish of urea crystals on his laboratory bench, produced by heating inorganic salts. Thus was born the field of synthetic organic chemistry.
Around the dawn of the 19th century, chemistry was in revolution right along with the rest of the western world. The study of chemical transformation, then still known as alchemy, was undergoing systematic quantification. Rather than rely on vague and mysterious incantations, scientists such as Antoine Lavoisier wanted to create what historian of science and technology Bruce Hevly calls an “objective vocabulary” for chemistry. Through careful measurement, a set of clear rules governing the synthesis of inorganic, non-living materials gradually emerged.
In contrast, in the early 1800s the study of organic molecules was primarily concerned with understanding how molecules already in existence were put together. It was a study of chemical compositions and reactions. Unlike the broader field of chemistry taking shape from alchemy, making new organic things was of lesser concern because it was thought by many that organic molecules were beyond synthesis. Then, in 1828, Wohler synthesized urea. Suddenly, with one experiment, the way scientists did organic chemistry changed. The ability to assemble organic molecules from inorganic components altered the way people viewed a large fraction of the natural world because they could conceive of building much of it from simpler pieces. Building something from scratch, or modifying an existing system, requires understanding more details about the system than simply looking at it, poking it, and describing how it behaves. This new approach to chemistry helped open the door to the world we live in today. Products of synthetic organic chemistry dominate our environment, and the design of those products is possible only because understanding the process of novel assembly revealed new principles.
It was this step of moving to Synthetic Chemistry, and then to an engineering of chemistry, which radically changed the way people understood chemistry. Chemists had to learn rules that weren’t apparent before. In the same way that Chemical Engineering changed our understanding of nature, as we begin engineering biological systems we will learn considerably more about the way biological pieces work together. Challenges will arise that aren’t obvious just from watching things happen. With time, we will understand and address those challenges, and our use of biology will change dramatically in the process. The analogy at this point should be clear; we are well on our way to developing Synthetic Biology.
Before going further, it is worth noting that this is not the original incantation of the phrase “synthetic biology”. Whatever the reception this time around, the first time it was a flop. In her history of the modern science of biology, Making Sense of Life, Evelyn Fox Keller recounts efforts at the turn of the 20th Century to discover the secret of life through construction of artificial, and synthetic, living systems; “To many authors writing in the early part of the [20th] century, the [path] seemed obvious: the question of what life is was to be answered not by induction but by production, not be analysis but by synthesis.”(Keller, p.18) This offshoot of experimental biology reached its pinnacle, or nadir, depending on your point of view, in attempts by Stephané Leduc to assemble purely physical and chemical systems that demonstrated behaviors reminiscent of biology. As part of his program to demonstrate “the essential character of the living being”(ibid, p.28) at both the sub-cellular and cellular level, Leduc constructed chemical systems that he claimed displayed mitotic division, growth, development, and even cellular motility. He described these patterns and forms in terms of the well-understood physical phenomena of diffusion and osmotic pressure. It is important to note that these efforts to synthesize life-like forms relied as much on experiment as upon theory developed to describe the relevant physics and chemistry. That is, this was a specific program to use physical principles to explain biological phenomena. These efforts were described in a review paper at the time as “La Biologie synthetique”(ibid, p.31-32).
While the initial reception to this work was somewhat favorable, Leduc’s grandiose claims about the implications of his work, and a growing general appreciation for complicated biological mechanisms determined through experiments with living systems, led to something of a backlash against the approach of understanding biology through construction. By 1913, one reviewer wrote, “The interpretations of M. Leduc are so fantastic…that it is impossible to take them seriously”(ibid, p.31). Keller chronicles this episode within the broader historical debate over the role of construction and theory in biology. History regards the folks in the synthetic camp, and related efforts to build mathematical descriptions of biology, particularly in the area of growth and development, as poorly regarded by their peers. Perhaps inspired by the contemporaneous advances in physics, it seems that the mathematical biologists and the synthetic biologists of the day pushed the interpretation of their work further than was warrented by available data.
In response to what he viewed as theory run rampant, Charles Davenport suggested in 1934 that, “What we require at the present time is more measurement and less theory…There is an unfortunate confusion at the present time bewteen quantitative biology and bio-mathematics…Until quantitative measurement has provided us with more facts of biology, I prefer the former science to the latter”(ibid, p.86). I think these remarks are still valid today. Leduc, and the approach he espoused, failed because real biological parts are more complex, and obey different rules, than his simple chemical systems, however beautiful they were. And it is quite clear that vast forests have been felled to publish theory papers that have little to do with the biology we see out the window. But theory, drawn from physics, chemistry, and engineering, does have a role to play in describing biological systems. Resistance to the tools of theory has been, in part, cultural. There has always been a certain tension in biology over the utility of mathematical and physical approaches to the subject;
To put it simply, one could say that biologists do not accept the Kantian view of mathematics (or, rather, mathematization) as the measure of a true science; indeed, they have often actively and vociferously repudiated any such criterion. Nor have practicing biologists shown much enthusiasm for the use of mathematics as a heuristic guide in their studies of biological problems.(Keller, p. 81)
Fortunately, this appears to be changing. Mathematical approaches are flourishing in biology, particularly in the interpretation of large data sets produced by genomic and proteomic studies. Physicists and engineers are making fundamental contributions to the quantitative understanding of how individual proteins work in their biological context. But I think it is important to acknowledge that not all biologists think a synthetic, bottom up, approach will yield truths applicable to complex systems that have evolved over billions of years. Such concerns are not without merit, because as the quotation from Charles Davenport suggests, biology has traditionally had more success when driven by good data rather than theory. The challenge today is to build quantitatively predictive design tools based on the measured device physics of real biological parts, and to implement designs within organisms in ways that work in the real world...