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Biology – A Systemic Redefinition?

The terms systems and are currently experiencing a boom – something that has already occurred several times in the . But what do they actually signify in scientific terms? Are they an expression of a far-reaching change within the discipline, or mere promotional buzzwords that simply “fill old wine into new bottles” in order to present it in a more palatable form? An analysis.

TEXT HANS-JÖRG RHEINBERGER

he terms and synthetic bi- imental means. In addition, it introduced to biolo- ology are experiencing an inflationary gy the practice of working with model , boom in the context of the sciences. and established a kind of experimentation that is Not only are they being appropriated by more or less the distinguishing feature of the field of research programs, databases, institutes biology – the crossing experiment as carried out by T and companies, but increasing numbers of scientists in the mid-19th century. are also using them to describe their work. Howev- This experimental revolution was accompanied er, as a look back at the history of biology shows, by a conceptual shift. In 1909, the term “” was there is nothing at all new about this phenomenon. introduced by Wilhelm Johannsen, who also was the Genetics became established as a special discipline first to differentiate between gene and characteris- within the field of biology in the early . tic, that is, between and . This In reality, it was more than that. It went on to devel- distinction proved to have far-reaching consequenc- es: it established a hierarchy for organisms based on interior and exterior, center and periphery, essence and appearance. The accompanying trend for gene- Genetics asks the centered thinking would leave its mark on the life sciences throughout the 20th century. basic questions about life The relationship between gene and characteris- tic enabled the investigation of fundamental ques- tions regarding the manifestations of life. However, op the claim of representing something akin to an the experimental processes available to classical ge- experiment-based general biology, a claim that it netics at the time didn’t enable scientists to explain succeeded in asserting. Genetics asked the basic ques- what consist of and, above all, how they influ-

tions of life, insofar as this was possible using exper- ence the expression of characteristics. > Photo: Birgit Schoeberl, Merrimack Pharmaceuticals

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Network map of a : Every consists of a nested network of smaller reaction pathways. Without such complex interconnections, life could not .

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Both of these questions were successfully tackled by riod and can be found gracing not only daily news- , which emerged around the mid- papers, but also scientific journals, including a spe- 20th century. What occurred at this point was more cialist publication that incorporates both terms in of a rupture than a seamless from classi- its title: Systems and Synthetic Biology. cal to molecular genetics. In the course of this mo- What the two terms have in common is that, lecular biology revolution, a new generation of bio- first, the new associated terminology, which would physicists, and identified be comparable to that originating in the periods of nucleic acids as the genetic material, and under- and molecular genetics and could stood as a of genetic in- be viewed as the harbinger of a new era, is not clear- formation into biological function. ly identifiable. Second, they are terms that have al- The subsequent development of molecular ge- ready been in vogue at various stages in the history netics into molecular had two further con- of biology. sequences: on the one hand, it pulverized the over- The term “system” signified different things at var- simplified “gene for” concept of classical and early ious stages in the history of the life sciences. The nat- molecular genetics, and, on the other, it led to the ural history of the 18th century was shaped and emergence of and anal- driven by a concept of system as an ordering cate- ysis. Genetic engineering and genome analysis, in gory for the diversity of life forms. Linné’s Systema turn, established a new form of molecular cell biol- naturae is representative of this trend. ogy, which provided a hitherto inconceivable abun- This changed in the late 18th century. Once the dance of applications. This new field was developed term biology was coined and an independent exper- and refined from the 1970s to the early years of the imental biological appeared on the scene, new millennium without the scientific the dividing line between physics, and bi- deeming it necessary to introduce new names for it. ology repeatedly ignited the debate as to how - This situation changed around the turn of the isms could be analyzed without losing sight of life millennium, at the time of the successful comple- itself. It could even be claimed, perhaps, that the as- tion of the and the failure sociated new system concept – in the form of a whole that is greater than the sum of its parts – ac- tually launched the idea of biology as a science in the first place. Immanuel Kant referred to living or- The supposedly modern terms were ganisms as “organized and self-organizing beings.” In the late 19th century, a debate between devel- in vogue previously opment mechanics, on the one hand, and more sys- temically oriented biologists, on the other, triggered a renewed debate on . The the- of a first wave of experiments in med- oretical work carried out in the systems biology of the icine. Since then, a profusion of new names for the early 20th century focused on concepts like steady next stage have been in circulation, many of which state and field. However, its proponents remained are derived from the term genomics: we hear talk of outsiders, for the most part; as theorists, they were transcriptomics, proteomics, metabolomics, and very much peripheral to experimental biology. even organomics. In the 1950s and 1960s, biological cybernetics But two terms stand out from all others: systems shifted the focus in biology from the molecular lev- biology and synthetic biology. Both terms have el to behavior, to systems-based thinking. In its gained enormous popularity within a very short pe- wake, molecular and Nobel laureate Fran-

14 MaxPlanckResearch 2 | 12 çois Jacob proposed the general concept of the inte- ganization of the biologists’ work and, therefore, a gron for the hierarchy of the feedback loops to parallel world of data production and processing – which organisms are subjected. Interestingly, simul- and less so the characteristics of the , the taneous to the emergence of genetic engineering in actual object of this work. If this were to be the case, the 1970s and the boom of the 1980s the question would arise, of course, as to how the and 1990s, the term cybernetics slowly but surely two worlds relate to each other. Unfortunately, disappeared from the biological literature, and con- those involved are making little or no effort to es- cepts like the were hardly adopted at all. tablish clarity on such issues. So what characterizes the current increasingly This brings us to synthetic biology. Once Louis forceful call for a systems biology? , Pasteur’s view that organisms arise only from exist- who was awarded the 2002 Nobel Prize for his re- ing seeds and do not spontaneously appear on Earth search on the genetic regulation of organ develop- ment in the roundworm , views it as nothing more than an empty buzzword. “Systems biology is not a science,” he stated cate- Is it about the organism – or the gorically in a recent interview. He expressed the view that the important new insights in the life sci- organization of scientific research? ences will continue to be gained through the tried and tested analytical modus of . A new generation of life scientists clearly takes a became established during the course of the 19th different view. However, clarification is urgently re- century, biology focused on the question as to how quired as to precisely what constitutes the systemic organic life could arise on Earth throughout the character of contemporary systems biology. Has the 20th century. To the present day, however, the cor- focus on the genetic level of organisms come to an responding syntheses have been merely fragmen- end? Are there new concepts that extend or even re- tary. And the current concept of synthetic biology place the repertoire of molecular biology – genetic relates only to the periphery of these approaches. program, structural gene and regulator gene? It ap- Scientists repeatedly referred to synthetic biolo- pears that concepts like that of the network, which gy over the course of the 20th century, initially in is widely disseminated in the sciences today, are far conjunction with synthetic chemistry. The aim of too general to assume such a role. this discipline was not only to recreate organic sub- Or is the use of the term systems biology justi- stances from existing elements in the laboratory, but fied by new laboratory and computer ? also to generate substances that don’t occur in na- Today, high-throughput technologies like DNA and ture in this form. chips and the new generation of sequencing The term was also used occasionally in connec- processes produce vast volumes of data on cellular tion with the initial successes of genetic engineer- processes. In this context, however, the term “sys- ing in the 1970s. However, it did not become wide- tem” is more an expression that refers to the im- ly established at the time. Instead, the terms mense volumes of data that are generated in the lab- genetic and genetic engineering took oratories with the help of chips and robots and that hold and went on to dominate the public debate for can no longer be evaluated without the help of com- three decades. puter programs. The boom in the use of the terms synthetic biol- What would be referred to here is thus primari- ogy and systems biology began only with the start

Photo: Birgit Schoeberl, Merrimack Pharmaceuticals ly a technical system – namely one involving the or- of the new millennium. Here, too, we must question

2 | 12 MaxPlanckResearch 15 whether this is merely a swapping of labels that is THE AUTHOR not scientifically motivated, and constitutes an at- tempt to steer public perception in a new direction. Or has there been a qualitative leap in the concepts and techniques for the manipulation of life as com- pared with the 20th century that would justify the adoption of a new name? The use of the term is vague. Today, the experi- ments by American researcher Craig Venter come under the term synthetic biology. Venter tries to re- create entire bacterial artificially and wants to use them to replace a natural genome. The term also covers the experiments carried out to define a minimal that would just suffice to Hans-Jörg Rheinberger, born in 1946, is a Director enable a bacterium to reproduce. at the Max Planck Institute for the Synthetic biology also includes the permanent in Berlin. His work deals primarily with the changes incorporation of biological-chemical subsystems to which the issues and experimental approaches into organisms that provide the latter with new in biology have been subjected over time. A native characteristics. In addition, the use of modified nu- of Liechtenstein, he studied biology and philosophy cleic acids as genetic material and the attempts to in Tübingen and Berlin, and is a member of the change the are also considered to be Berlin-Brandenburg Academy of Sciences and the synthetic biology. German Academy of Sciences Leopoldina. But don’t all of these cases merely involve the application or further development of technologies that, until ten years ago, were referred to as genetic the adoption of a new linguistic label in response to the widespread skepticism toward genetic engineer- ing with a view to attracting new funding. The other scenario is that the life sciences actual- The new linguistic label responds ly are undergoing a transition on a scale that is eclips- ing molecular biology and the recombinant DNA to the general skepticism technologies of the last century, and heralding a new era of biological controlled by people. If this is the case, Darwin will ultimately be over- engineering or, more generally, ? taken by his own analogy. As is generally known, he What is the reason for this new self description? based his theory of natural evolution on the model Two scenarios are conceivable. The first and of artificial selection familiar to him from the - more controversial of the two would be that the soft ers of his time. Today, we may well be facing a situ- concept of synthesis is used today to encourage a ation in which the breeders (“designers”) of our time more positive attitude to the deliberate and perma- are really getting down to business. However, this

nent modification of living organisms, and involves would require an entirely different debate. Photo: Birgit Schoeberl, Merrimack Pharmaceuticals (top), MPI for the History of Science (small photo)

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