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When the metaphor of the ‘program’ first appeared in the published literature of molecular biology in the early 1960s, very little was known on a molecular basis about how different genes actually work in development. The genetic program was a story in a nutshell that explained comprehensively in advance how genes could organize development and make life possible. If the genome contains only information (a sequence of four different nucleotides), an explanation was needed of how organisms can be made of information, i.e. how the 1-dimensional sequence of components of the DNA polymer can be transformed into a 3- or 4-dimensional reality of an organism. The program was the key idea.

The notion of the ‘gene’ originated much earlier, but in another context. It was the problem of inheritance not development that first led biology to talk about genes. Johannsen's famous definition in 1909 [13] aimed at the factors – whatever their precise nature may be – that can be passed on by egg and sperm and determine the traits and characteristics of the next generation of organisms. The gene was an answer to what we can dub the ‘bottleneck-problem’ of biology [14]. This problem is located within the gap between the generations. How can the form and structure of a species in one generation be rebuilt from the two tiny germ cells that are passed onto the next generation? Oocyte and sperm fuse and build together one single cell, the zygote, which must be capable of developing into the whole new organism. What component of the oocyte can be responsible for this? A major discovery was that it is not the membranes, not cytoplasm, not the proteins, but nucleic acid, essentially the nucleic acid contained in the chromosomes. Chemically it is DNA, a double-stranded, enormously long molecule shaped as a double helix. Rosalind Franklin, James Watson and Francis Crick discovered its chemical structure in 1953. The implication was, however, that a sequence of only four different building blocks, the nucleotides, must be the key responsible element in heredity. How can that be possible? How can a sequence, or the information contained in the sequence, guide development? The bottleneck-problem was tightened from a cellular level to a molecular one.

Information is essentially a pattern of differences that can be reliably translated into another pattern and therefore can be said to determine the second pattern. However, genetic information was not thought to be semantic in the sense of carrying an intention to represent this second pattern. It is neither the previous generation that encodes an intention within its genetic information, nor any spirit in nature, nor God. This is very important to keep in mind. The notion of genetic information was not thought to be intentionalist but purely mechanical.

Before developmental geneticists in the 1980s and subsequently could investigate more and more of the actual mechanisms of developmental processes, and elucidate the precise roles that different genes and gene products play, two of the most productive molecular biologists of the earlier time, François Jacob and Jacques Monod, in a historic paper of 1961, used the term ‘program’ to explain how the imagined development was possible. The paper was about their discovery of gene regulation in bacteria, the Lactose operon. In the concluding section they observe:

‘The discovery of regulator and operator genes, and of repressive regulation of the activity of structural genes, reveals that the genome contains not only a series of blue-prints, but a co-ordinated program of protein-synthesis and the means of controlling its execution’ [15, p 354].

Protein synthesis was the essential process for the development and life of the organism. As we will see later, the crucial part of this quote is the statement that ‘the genome contains’ the program. DNA contains a program for development, and therefore the cells can execute this program if they are properly equipped. The genome, according to Jacob and Monod [15, p 221], even contained the means of controlling its execution [4, 5]. The DNA molecule was thought of as a central organizer of all essential steps in the life of the organisms. The Lactose operon provided an example of how this could work: genes are regulated by regulator molecules that are again synthesized from other genes. The genome is a self-regulatory system controlling the development and behavior of the cell.

In the same year, 1961, another biologist who was more preoccupied with evolution and inheritance than biochemistry, Ernst Mayr [16], published a somewhat similar idea also using the program metaphor. But for him, the metaphor served other needs. His problem was teleology, i.e. the question of how it can be thought possible within a strictly Darwinian framework that allowed for no reference to vital forces, that organisms are such miraculously well-functioning constructions and show goal directed behavior. The assumptions of Modern Synthesis Darwinism combined the molecular evidence of DNA-copying and the ‘central dogma’ of molecular genetics (information flow goes from nuclear DNA to protein, not back from proteins into DNA) with the Darwinian mechanism of random variation and the survival of the fittest. This excluded the possibility of inheriting phenotypically acquired functions from the previous generation. Everything had to be in the genes. The solution that Mayr saw was given by the idea of a ‘genetic program’. If the previous generation passes a program to the next, containing all the information that the system needs to reconstruct itself and to behave, then we do not need any more assumptions to explain an apparent goal-directedness in development and behavior. Programs evolve by chance and selection. Teleology, the obscure old doctrine of nature following certain aims, could be replaced by a cybernetic model of goal-directed, negative feedback systems, or ‘teleonomy’ [4, pp 196, 221; 16]. The processes seem to be goal-directed, but this is only their appearance to us. Actually, development is programmed by DNA information, and it is the program that is passed onto the next generation, perhaps including mutations that may give advantages or disadvantages to the organism and to its chances for reproduction.

This was an argument against vitalism. Vitalism was a basically metaphysical doctrine arguing on the level of ontology. It claimed that living processes contain a nonphysical force or principle that make them what they are, which can never be explained by the physical sciences. Therefore, in Mayr's text, the assumption of the genetic program was also a metaphysical argument, working on the level of ontology. It explained how is it possible that living beings come into existence, and their way of existing in the world. In terms of theory building, the idea of the genetic program replaced intentionality in nature and the vitalist non-physical forces. It was therefore negative metaphysics that Mayr was arguing for. With the physically plausible assumption of a genetic program it was no longer necessary to believe in nonphysical forces and intentions to explain the apparent functional organization and goal-directed behavior of organisms. Jacob and Monod [15] were comparatively more constructive in their approach. They saw how such a genetic program could be conceptualized: as a sequence of regulatory steps whereby genes are regulated by the products of other genes.

But was this discursive move to the programs containing genome just a step towards dropping unnecessary metaphysical ballast and therefore in itself ontologically or metaphysically ‘innocent’ or neutral? I do not think so. In order to see this, we need to advance another 45 years in the history of biology and look at the ideas of contemporary systems biology. Kunihiko Kaneko, a Japanese biologist and influential theorist of complex molecular systems, summarizes the current approach to explaining the emergence of relatively stable and regular developmental pathways of organisms in a very simple way as follows:

‘Thus the situation is one of mutual influence, not unidirectional causation. Hence, although the genes can be thought of as in some sense controlling such processes, in fact it is not true that an understanding of the genes alone is sufficient for their complete description. For example, even if we were somehow able to obtain the DNA of a dinosaur, unless we also knew the initial conditions of the cellular composition that allow their proper expression of genes, we would not be able to create a Jurassic Park. The conclusion we reach from these considerations is that… we should be studying models of interactive dynamics. Then, we should inquire whether, within such dynamics, the asymmetric relation between two molecules is generated so that one plays a more controlling role and therefore can be regarded as the bearer of genetic information’ [17, p 20].

If we compare this idea that Kaneko is outlining, referring to vast experimental evidence and to mathematical models, with the image inherent in the ‘genetic program’, several important differences become obvious. The relation between different molecules and processes in the cell are seen as mutual influence, instead of a unidirectional causality contained in sequences of linear if-then events. Parts interact in many ways, loops of causal influence going forward and backward, branching in many directions and making the system as a whole relatively open or relatively closed. The division of roles within such a system is not a precondition, but must itself be explained as a result of the interactive dynamics of the system. Therefore, the apparent specialization of DNA as the bearer of genetic information, and the many very important roles singular genes can play in the development of the organism, are products of the interrelation of the parts of the system and their dynamics. This is the second striking difference to the genetic program approach. There, it was thought that a causal program is a precursor of development in the shape of the sequential composition of the DNA polymer. Thirdly, a regularity of developmental events that could be described as something like a program is to be located on the level of those interactive dynamics, not on the level of one component of the system. In terms of the distinction between genotype and phenotype, the assumption of systems biology is that the program (if anybody still wants to talk of programs) is a phenotypic regularity. What behaves regularly in foreseeable and reproducible sequences of events is the whole organism within an environment, not one isolated molecule.²

Molecular genetics, particularly in the context of developmental biology and genomics, has contributed to this enlargement of the picture. A wide variety of mechanisms that enable the cell to use DNA sequences in different ways have been discovered. The active RNA molecules (still suggestively called ‘messenger’ RNA) are compiled in much more complicated ways, and most of the RNA molecules (MicroRNAs) are no templates for proteins at all. DNA sequences that code for proteins (containing the genes in a classical sense) and some proteins are multifunctional. Which effects will be realized depends on a multitude of other factors, and sometimes on spatial information as well, i.e. on the place within the cell or a multicellular network. Some genes overlap, some genes can be spliced in multiple ways, depending on the situation, and the resulting RNA variants will lead to different proteins that are all related to the same DNA stretch. Sometimes the cell uses fractions of one and sometimes fractions of the other of the two single DNA strands as a template for producing a functional RNA. There are also switches to alternative reading frames, i.e. the shifting of the three-letter code by one, resulting in different sequence information. There is sometimes even post-transcriptional editing of mRNA, i.e. the introduction of changes in the sequence of an mRNA molecule after its composition, which also leads to a different amino acid sequence of the protein being built from it [14, 19-22]. Genes are multifunctional [23], and therefore they can no longer be considered as independent factors in a chain of events. But this is precisely what the idea of the ‘genetic program’ suggested.

Taking these and other phenomena into account, Eva Neumann-Held [24] has reconsidered the very concept of the gene from a systems perspective. If we still want to call what explains the biosynthesis of a particular type of protein in a cell a ‘gene’, we can no longer say that one stretch of DNA is responsible. It is rather a range of factors, interacting with DNA and with each other, and processes sometimes transgressing the boundaries of the cells and the body, that are actually contributing. This set of contributing factors includes DNA, but also much else. Neumann-Held bases her reflection on a groundbreaking book by Susan Oyama from 1985 that has the title ‘The Ontogeny of Information’ [25] and has inspired many authors to new formulations under the umbrella term of a ‘developmental systems approach’ [26, 27]. The key idea was a new attempt to theorize development. Previously, we thought development was basically a result of two different information resources, one internal and genetic, the other external, i.e. social, environmental, or cultural. The divide between these two information resources has materialized in the ‘nature or nurture’ debate in developmental psychology. One school emphasized the genetic contributions (sociobiology, evolutionary psychology, etc.), the other more the social and cultural factors. Oyama's point was that development is better seen as an interaction of both, but not in the sense of an interaction between two independent types of factors. There can be no genetic factors without the environment, and there can be no environmental factors without an organism and its internal resources. Both are mutually related, so that we should avoid making a distinction between those two classes of contributing factors. From this, Oyama came to a different understanding of genetic information as developmental information. Developmental information itself has a developmental history. With reference to Gregory Bateson's [28] famous definition of information as ‘difference that makes a difference’, she explains: Genetic information ‘neither preexists its operations nor arises from random disorder. … Information is a difference that makes a difference, and what it “does” or what it means is thus dependent on what is already in place and what alternatives are being distinguished’ [25, p 3].

Genetic information, in the sense of developmental information, is itself'developmentally contingent in ways that are orderly but not preordained, and if its meaning is dependent on its actual functioning, then many of our ways of thinking about the phenomena of life must be altered’ [25]. Following this line of thought, biology's basic picture is being transformed.³

The program view assumed that the development of the complex organism we see in the biosphere depends on the existence of genetic information, which can be copied and reproduced from a template. It said that the generations do not transmit a small prototype or the adult structure to the next generation, and no supernatural intentions or forces are necessary for a comprehensive explanation of the development of a new generation. What is transmitted is a list of instructions for making that structure [29, p 2]). The systems view by contrast sees that in fact it is the entire cell that is reproduced, not only some lists of instructions. The cells reproduce not because the genome contains instructions for building it, but

‘because any inheritance involves passing on DNA and all the cellular and extracellular structures, processes, and materials necessary for its exploitation’ [25, p 77].

Information can therefore be seen in at least two different ways: either as something inherent in a pattern that is transmitted or as something that is itself a product of interactive dynamics. Accordingly, two different ontologies of living phenomena are put forward.

But they are not equivalent offers, from which we could choose one arbitrarily. There are today serious reasons for preferring the systemic approach. The most compelling of these comes from science itself.

If information for development is a product of interactive dynamics, it does not exist before the development of the system actually takes place. Developmental information continually emerges from the interactive dynamics of the cellular (or multicellular) system and – we need to allow this conclusion as well – continually fades away afterwards. In this sense, genetic information is contingent and ephemeral. DNA is an inert and relatively constant molecule, a source of stability for the system and highly important in many ways, but DNA is not the carrier of developmental information. We can say that the organism is essentially a self-informing system. The whole system develops and behaves regularly and predictably in many ways, but the regularity is not a result of a preexisting program.

This theoretical rereading of the molecular evidence in terms of systems cannot take away any of the empirical evidence that we have about the causal involvement of DNA sequences or mutations in the development of certain characteristics like diseases. The systems view, as I understand it, is not an argument against genomics, medical genetics or against DNA-related research in any way. The argument does not work on the level of experiments or empirical work, but on the level of the interpretation of the empirical evidence, which can be seen as plausible or implausible.