We recently bought the most enchanting bonsai. As I stood there mesmerized and spellbound by its elegant spatial architecture – I couldn’t help but wonder how on earth is this elegant form and architecture choreographed from a simple seed? How is this dynamic living symphony of bio molecular and cellular processes, orchestrated into such a wonderful coherent structure? The instinctive answer that jumped to mind ready to dismiss my curiosity, awe and wonder with a sense of condescension was DNA – the blueprint to life. I could hear the voice of Richard Dawkins, “It is easy to think of DNA as the information by which a body makes another body like itself. It would be more correct to see a body as the vehicle used by DNA to make more DNA like itself”. No mystery, no awe, no mysticism just DNA as the book of life.

However I felt uneasy about such an answer. My suspicion was driven by what I knew about deoxyribonucleic acid (DNA) from my organic chemistry days as a student. My imagination failed to see how from such a molecule, as exquisite and marvellous as it is, how it could contain any of the steps necessary to choreograph the spatial form and architecture of a bonsai. After all DNA is a molecule consisting of a ribose sugar base, phosphate backbone and any one of four nitrogen bases which can link up to form anything from a thousand to a billion base pairs in sequence. Perhaps I was missing the principle thing that makes DNA famous – information! And of course my failure to imagine how exactly DNA could lead to the extravagant and diverse forms of organisms was not a guarantee of its truth – my imagination has failed me quite often. So perhaps I needed to understand how the basic doctrines of the central dogma of biology work. What I discovered was surprising in one sense, and yet not so surprising in another. Surprising in that the popular idea of the genetic program or DNA being the blueprint to life or the “selfish gene” is “without clothes”. Why it was not surprising in another sense is that our current scientific philosophy is mechanistic and therefore committed explicitly and implicitly to a reductionism of all phenomena to a more “fundamental” set of physical rules. And it is quite obvious, that there is something magical and enchanting and autonomous about life that rebels against the paradigm of being reduced to “nothing but chemicals”.

The discoveries that I will be sharing involve: debugging the genetic program metaphor; some empirical insights on how cells govern their behaviour and development beyond the gene; some implications for the dominant Darwinian view of life; and lastly a brief look at how the ancient philosopher Aristotle can give us some insight about understanding what life is.

Debugging the genetic program

It was Jacques Monad and Ernst Mayr who captured with an eloquence to rival any poem, the metaphor of the genetic program. Wells retells the story:

“In 1970, Jacob wrote that an organism is the realization of a “programme génétique” (genetic program) written in DNA sequences [7]. The same year, Monod wrote that “the sequence of nucleotides in a DNA segment entirely defines the sequence of amino acids in the corresponding polypeptide [protein].” And since “the polypeptide sequence specifies completely (under normal initial conditions) the folded structure that the polypeptide adopts once it is constituted, the structural and hence functional ‘interpretation’ of genetic information is unequivocal, rigorous. No supplementary input of information other than the genetic is necessary; none, it seems, is even possible”[i].

A decade earlier Enrst Mayr had articulated the idea of the genetic program: “Where, then, is it legitimate to speak of purpose and purposiveness in nature, and where is it not? To this question we can now give a firm and unambiguous answer. An individual who-to use the language of the computer-has been “programmed” can act purposefully. Historical processes, however, cannot act purposefully. A bird that starts its migration, an insect that selects its host plant, an animal that avoids a predator, a male that displays to a female-they all act purposefully because they have been programmed to do so. When I speak of the programmed “individual,”I do so in a broad sense. A programmed computer itself is an “individual” in this sense, but so is, during reproduction, a pair of birds whose instinctive and learned actions and interactions obey, so to speak, a single program.”

He continues in the article to say:

“The purposive action of an individual, insofar as it is based on the properties of its genetic code, therefore is no more nor less purposive than the actions of a computer that has been programmed to respond appropriately to various inputs. It is, if I may say so, a purely mechanistic purposiveness.”

Others up to the present day have continued to follow suit capturing the core tenets of genes as the blueprint to form, “genetic informationism (“genes contain the entirety of the preformed, species-specific developmental ‘information’”), genetic animism (“a genetic programme in the zygotic DNA controlling the development of an organism”), and genetic primacy (“the gene is the unit of heredity, the ontogenetic prime mover, and the primary supplier and organizer of material resources for development, such that the phenotype is the secondary unfolding of what is largely determined by the genes”) (Robert, 2004, 39)” [ii]

What Monad, Mayr and others are claiming is that DNA is in the metaphor an information storage device. DNA (deoxyribonucleic acid) is an incredible organic molecule known as a nucleic acid. It consists of 3 basic molecules: phosphoric acid which binds to a deoxyribose sugar and a nitrogen containing base of which there are four different types These 3 units combine to form a single nucleotide. DNA consists of nucleotides which can link up to make up to a billion nucleotides in sequence. Each group of three successive nucleotides forms a codon and each codon represents an amino acids. Amino acids are then strung together to make a protein which folds and takes on a three dimensional spatial shape which a unique function. Proteins are the workhorse molecules of organisms involved in every imaginable process essential to organisms. Thus by specifying proteins which come together to weave the intricate processes assumed eventually to lead to the beautiful living forms of things like bonsai trees, DNA has the privileged position of being the blueprint, the genetic program containing all necessary and sufficient information to construct the organism.

It is important to note that the metaphor was trying to solve a number of conceptual problems that emerged with the mechanistic view of nature championed by early modern philosophers and scientists such as Descartes, Newton and Galileo. The first problem is how do we explain the purposive, teleological and goal directed behaviour that organisms clearly exhibit if the world is intrinsically devoid of purpose? If nature is purely mechanistic how do purposive phenomena emerge? The second problem how does development of the organism from a single cell to a complete mature organism occur? How does the form of the organism arise? It is this second problem that will be the focus of my essay.

The organism choreographs its own dance steps

I came across an insightful review article by Franklin Harold where his aim is to restore the cell itself as a whole back into the privileged position of being the basic organizing unit of life rather than the genome which is an essential part of the whole. His article focuses on the cell and he asks how does the form and spatial architecture of the cell emerge? Is it spelled out by the genome? Is there a genetic program that spells out the spatial architecture of the cell? His focus is on cell architecture rather than plant shape and form which are immeasurably more complex and so the problems he encounters can only be compounded exponentially when thinking of more complex organisms. The cell presents however a good starting point as to how form arises.

DNA is a parts list rather than a controlling program

Genes specify the parts but not the arrangement of the parts into higher order hierarchies.

“Spatial organization is not written out in the genetic blueprint; it emerges epigenetically from the interplay of genetically specified molecules, by way of a hierarchy of self-organizing processes, constrained by heritable structures, membranes in particular. Molecules and the genes that specify them remain essential since they constitute the material basis of all biological structures, but from the perspective of organized systems they do not hog the limelight. Centre stage is held by the whole cell, that indispensable unit of life, of which molecules are but parts; the smallest self that truly organizes itself is the cell.”

Think of the construction of a building, the bricks, doors, windows, cements are all necessary parts of the building however they must still be arranged and organized into a specific pattern. Similarly DNA actually specifies the molecular parts, rather than being a blueprint containing the organization of the whole organism. This directly contradicts what the genetic program claimed, namely that DNA specifies completely all information required for the organism to develop. DNA is more of a recipe that only specifies the ingredients, or the parts and not what to do with them or in what pattern and order to put them together in. A point he repeatedly makes throughout the article, “…the many genomes now on record apparently contain no genes that specify cellular forms and patterns. Genes specify the molecular parts, not their arrangement into a higher order.” Marshall in his review of how cells count and measure size agrees with Harold, “The genome only encodes a parts list for the cell, specifying when each protein gets made and at what quantity“.

There are no “morphogenes” that direct the morphology of organisms

Harold reviewed work done on morphogenes and finds that experimental results fall far short of the claims that genes encode the form and architecture of organisms. Morphogenes are genes which when mutated in the organism by either preventing their expression an abnormal and defective form of the organism occurs – thus the idea is that morphogenes are involved in morphology of the organism. Harold argues that this however in now way explains how form whether normal or abnormal actually occurs. Another claim is that the morphogenes are either enzymes, structural proteins for cellular organelles, or signalling proteins – there are no privileged proteins that control and direct the other proteins during morphology. The form of the organism Harold argues is not the direct product of a genetic code but rather of “proximal physiological processes”.

“For the most part, morphogenes encode quite mundane proteins, elements of the catalytic or structural ensemble. There is no obvious ‘genetic program ’, no clear distinction between one subset of genes whose products execute morphogenesis and another subset that directs the operation…If one cannot distinguish genes whose products govern the work from those that execute it, what meaning can one assign to the glib assertion that this or that gene ‘controls’ some particular process?”[iii]

A similar point is made by Mammato et al, that mechanical forces are as important in shaping and affecting the development process. What is important to note is that mechanical forces do not act on single genes but on a larger scale of cellular physiology, “Although soluble factors clearly are important contributors to developmental control, more recent studies have revealed that mechanical forces generated within the cells and tissues of the embryo can provide regulatory signals that are equally as important as those conveyed by chemicals and genes.”[iv] In their abstract they state their main findings after reviewing numerous research work, “Many of the genes and chemical cues that mediate tissue and organ formation have been identified; however, these signals alone are not sufficient to explain how tissues and organs are constructed that exhibit their unique material properties and three-dimensional forms”. Genes and their products (proteins and other molecular parts) are necessary but insufficient for how organs and tissues develop. The take home point is simply that:

 “There are no known genes that individually encode large amounts of information specifying the structure or patterns of development…there is no sign that an analogous network of genes maps out spatial organization at the level of single cells. Note especially that nothing resembling a program for morphogenesis can be identified in the many microbial genomes now on record.”[v]

DNA itself is controlled rather than it controlling and regulating

DNA is acted upon by other factors in the cell. It is inert until the organism activates and controls certain parts of it that are relevant to whatever task it requires. “DNA sequences do absolutely nothing until they are triggered to do so by a variety of transcription factors, which turn genes on and off by binding to their regulatory sites, and various other forms of epigenetic control, including methylation of certain cytosines and interactions with the tails of the histones that form the protein backbone of the chromosomes. All of these, and the cellular, tissue and organ processes that determine when they are produced and used, ‘control’ the genome”[vi]

Self-organization of complex structures is not controlled by genes

Self-organization as a basic principle of cellular activity demonstrates that genetic subunits do not determine complex cellular activities and structures. Harold defines self-organization as, “…the emergence of supramolecular order from the interactions among numerous molecules that obey only local rules, without reference to an external template or global plan…The definition explicitly excludes order imposed by an external template, whether physical (as in a photocopier) or genetic (as in the specification of an amino acid sequence by a sequence of nucleotides)”[vii].

A pervasive characteristic of organisms which pervades every level of life is self-organization. It is a phenomenon where supramolecular order arises from interactions of numerous subunits which make up the supramoleculur order or structure. The structure arises without input from some external template directing its organization such as a genetic template or program. In other words these high level structures arise not because there is some genetic program directing and co-coordinating their construction, but rather somehow they self–organize their parts into a coherent structure. Examples of self-organizing structures would be the mitotic spindle which is a fascinating complex structure responsible for dividing genetic material into two equal parts during cell division. It is composed of microtubules, chromosomes and accessory proteins. Some quotations on the mitotic spindle in literature confirm the fact that self-organization is a basic category in cells:

“The spindle arises from self-organization of microtubules and chromosomes, where the dynamics of the components help them explore the space and eventually get near each other so that they may interact. Self-organization of the spindle occurs through two main processes: formation of microtubule bundles and kinetochore capture by microtubules…The spindle arises from self-organization of microtubules and chromosomes, together with a variety of accessory proteins, whose different types of motions help them explore the space and interact with each other…Self-organization of the spindle occurs through two main processes: formation of microtubule bundles and kinetochore capture by microtubules“[viii]

Self organization also does not necessarily refer to static structures but dynamic and transient structures that respond to changing conditions. Self organization of structures and processes also always occurs in the context of a cell where direction, orientation and polarity is necessary for the structure, Harold makes the point “few if any of the complex internal structures can arise solely in obedience to local rules, without reference to the function of the whole cell. Spindles, we know, form at particular locations, and cells go to great lengths to ensure their correct orientation; accurate division hinges on it…The only self that can truly be said to organize itself is the cell”[ix]. Self- organization demonstrates that the although DNA and genetic products like protein are necessary they are not sufficient for determining the assembly of complex essential cellular structures like the mitotic spindle. There is not genetic program or blueprint that determines the self-organization of cellular structures. Additionally self-organization occurs within the context provided by the cell. Self-organization provides another illustration of the myth of DNA as a blueprint to life.

Dynamic processes cannot be reduced or encoded by static and fixed blueprints

The cell consists of dynamic processes such as cell division which requires flexible and dynamic components to complete the process. Dynamic processes cannot be coded for by static sequences. An analogy should elucidate this subtle point. A blueprint is itself an abstraction of the actual thing. The blueprint of a building is an abstraction of the actual building – it captures certain properties of it and leaves out others. It captures the end fixed product but not the dynamic construction process. The blueprint does not have information about how to mix cement, how long to leave the foundation, when to start with walls. It does not specify what type of machinery you will need: cranes, scaffolding, trucks and spades. The dynamic process of construction could never be captured by a blueprint, because the majority of necessary details which change with time are left out. Similarly the dynamic processes of cells could never be captured by a fixed static blueprint in the genome, a point Marshall articulates:

“Blueprints are excellent tools that encode the organization of a static system, in which every component has a fixed number, size, and position. A blueprint encodes all this information explicitly, and once the information is translated from the blueprint into the structure, the blueprint is no longer required. But unlike most human-made structures, living systems are dynamic, undergoing constant change and turnover. Such structures are less suitable to being specified by a fixed blueprint, requiring instead a more flexible means of dictating form.”

 One committed to the genetic program could argue that the genome is a blueprint in that it contains the set of instructions on how to build and assemble the organism. Think of a cake recipe and how it contains step by step instructions on how to get from the ingredients to a final product. The recipe is fixed and static in that the paper it is written on does not change with time – however it contains information that is dynamic. Take 2 eggs and stir, add 10g of flour etc. With each step the product changes until eventually the final product is reached. A dynamic process captured by a static fixed recipe. Such a response would only serve to further illustrate the privileged status of the cell rather than DNA. In the case of a recipe; until some agent with the ability to act dynamically follows the instructions, nothing can result from the recipe. It being a static, fixed and unchanging set of dynamic sequential instructions requires a dynamic agent to bring about those instructions it contains. Someone must follow step 1, and then step 2, take the eggs shake them for some time etc. Similarly DNA if it did contain sequential instructions on how to construct an organism would require some dynamic whole unified agent to follow and coordinate those instructions in time.

Diverse and distinct cell types contain the same DNA

Multi-cellular organisms like humans consist of diverse and widely different cell types; blood cells, liver, neurons, kidneys all these organs require completely different types of cells which paradoxically contain the same identical DNA. How does the exact identical DNA copy in each cell produce the remarkable differences in cell type behaviour, form and function? Each unique cell type has a radically unique pathway from when the organism is a single celled zygote; and as it develops and matures through successive cell divisions and differentiations eventually giving rise to unique and diverse cell types – each containing still the same DNA copy. The problem is how can the same DNA copy contained in each cell type cause the differences in the cell types? Suppose we say that DNA contains genetic instructions for how to differentiate into some Cell type A and Cell type B. The problem remains as to how the cell knows whether to follow instructions A or B? Why does every cell not follow instructions for cell type A then? DNA could not cause any cell to follow instructions A rather than B, the cell itself must decide. However if the cell decides and knows which instructions to follow, that means it actually already knows which cell type it is already independently of its DNA– and DNA becomes a means to that end. The cell knows that to become cell type A, it must express DNA in some particular way. Imagine a piece of paper with two sets of directions, one to location A and another to location B. Two people are given the same paper – one ends up in location A the other in location B. Obviously they each followed the instructions on the paper – however it was not the paper itself which determined where they end up because they could have chosen different instructions to follow.

Talbot eloquently summarizes this point, “The cell is an activity, with its own spatial and temporal patterns of behavior. And these patterns of behavior, situated within the choreography of the larger organism and its environment, are what hold the cell lineage together as a unified and well-directed process of differentiation”

Noble makes a similar point remarking on how the same identical DNA is expressed differently and contextually according to the needs of each particular cell (in multi-cellular organisms). The expression of DNA is not contained in the DNA itself but by each unique cell which knows its end, “The inheritance is robust: liver cells make liver cells for many generations of liver cells, at each stage marking their genomes to make that possible. So do all the other 200 or so cell types in the body (Noble 2006, ch. 7). Yet, the genome is the same throughout. That common ‘digital’ code is made to dance to the totally different instructions of the specific cell types.”

DNA is one amongst many essential parts that is inherited during the origins of a new cell

DNA is not the only organelle (cell component) that is inherited and passed down to the next generation of cells. Membranes are important and inherited as well, as the following quote illustrates the significance with great clarity:

“…biological order is distributed over several parallel and mutually dependent systems such that no one system, and certainly no one molecule, could reasonably be accorded the status of being a program, blueprint, set of instructions, and so forth, for the remainder.” For example, cells are structurally and functionally compartmentalized by a complex network of subtle membranes. These membranes regulate the role of gene products (proteins) within the cell and organism by, among other things, controlling the movement of proteins toward different functional compartments. Yet, despite their central importance in the cell, the membranous bodies cannot be reduced to the usual terms of genetic explanation. They “constitute the necessary and irreplaceable templates of their own production and reproduction, are passed along from one generation to the next [extragenetically, via the egg cell], and provide the unavoidable context in which DNA can be adequately interpreted, that is, in which genes can be genes.[x]

The most obvious and basic truth of biology – It takes a cell to make a cell! Harold reiterates this obvious point, “As a cell grows, divides, or changes form, it models itself upon itself. New gene products are released into a molecular society that already has spatial structure, and this framework ensures that placement of new molecules is congruent with the old order“. Noble in his article makes a distinction between digital information found in DNA and analogue information found in the other cellular machinery. DNA he terms digital because it represents stored and compressed information for making proteins. Analogue information however cannot be stored or said to be a representation – it is the actual thing itself, as Noble says, “It [cell architecture] itself is the self-sustaining structure that we inherit and it reproduces itself directly. Cells make more cells, which make more cells (and use DNA to do so)”[xi]. Cell architecture is directly passed down from existing cell architecture and does not arise from DNA.

A basic point in biology is that the cell provides the framework for DNA to function, “The cell as an organized three dimensional entity is the prior condition by which the template function of DNA “can make sense.” Information is not indigenous to DNA, it is constituted in the specific conditions of a cellular environment which is always already there. And if it wasn’t there, there is not an iota of evidence to think that the sequence of base pairs of nucleic acids in the DNA could provide the direction for reconstructing it.”[xii]

Other quotes only strengthen the point that DNA is unjustified in its privileged position, “…the empirical differences between the role of DNA and that of cytoplasmic gradients or host-imprinting events do not justify the metaphysical distinctions currently built upon them. Nucleic acid sequences and phospholipid membranes both have distinctive and essential roles in the chemistry of life and in both cases there seems no realistic substitute for them. But the facts of development do not justify assigning DNA the role of information and control while inherited membrane templates get the role of ‘material support’ for reading DNA[xiii]”

The point is that DNA requires a cellular framework in which to function, it cannot make that framework and hence the cell itself passes down the framework to the next cell generation.

There is no genetic program for forming organs like the heart

“Are there problems with claiming that genes contain all of the developmental “information” to form vertebrate hearts? Is there a genetic program in the DNA controlling heart development? Are genes the primary supplier and organizer of material resources for heart development, largely determining the phenotypic outcome? Existing studies of heart development have identified a role for fluid forces in specifying the internal form of the heart (Hove et al., 2003) and its left/right asymmetry (Nonaka et al., 2002). Additionally, biochemical gradients of extracellular calcium are responsible for activating the asymmetric expression of the regulatory gene Nodal (Raya et al., 2004) and inhibition of voltage gradients scrambles normal asymmetry establishment (Levin et al., 2002). A number of genes are also critical to these processes (Hamada et al., 2002) but the conclusion seems to be that genes do not carry all the “information” needed to generate form features of the heart.[xiv]“

Denis Noble makes a similar point drawn from his observations of heart behaviour. He looks at cardiac rhythm of the heart and concludes, “all the proteins involved in cardiac rhythm are encoded by the genome, but these alone would not generate rhythm. This is the sense (see above) in which I maintain that there is not a program for cardiac rhythm in the genome.”[xv]

Not only is there no genetic program detailing how the heart or cardiac rhythm should function, given all the parts they would not spontaneously emerge and the reason he offers relies on a bit of maths. You can describe and model the cardiac rhythm of the heart using differential equations – however to solve them requires specifying boundary and initial conditions. Those conditions are constraints which come from the cellular structure and not from DNA, “…Without the constraints imposed by the higher level structures, and by other processes that maintain ionic concentrations, the rhythm would not occur.”

200 genes (proteins) involved in various retinal diseases have been identified however there is no genetic program that the proteins direct in forming the eye, it seems to self-organize without any external direction from genes directing its formation. “Remarkably among these 200 or so genes known to cause retinal pathologies very few (if any) have been identified which might be construed to be anything more than ordinary structural or functional components of the mature photoreceptor. There is no genetic evidence that any of the genes expressed in the photoreceptors causing dysmorphologies are morphogenes in Franklin Harold’s sense[14,15] that is, genes whose primary function is directing or supervising the deployment of the constituents of the photoreceptors into their complex three-dimensional native cellular architectures.”

Summary

There is no genetic program that directs and controls the development of the organism from a single cell to a mature adult. At best some sections of DNA contain a protein template that the organism can use to create a specific protein. DNA is a parts list rather than a program – it requires a cellular context in order to be functional. DNA is one sub-cellular structure that is inherited when a new daughter cell is made. There is no genetic information present in DNA on forming particular organs like hearts or their essential behaviours. Membranes and cell architecture cannot be encoded in DNA, and therefore a new daughter cell inherits and makes its membranes and generates its cellular spatial architecture from previous membranes and cell architecture. In addition self-organization is a ubiquitous feature demonstrating that complex structures assemble within the cell without being directed by a genetic program. The science is clear – DNA as the blueprint for life is a myth.

“…there is no clear, technical notion of “information” in molecular biology. It is little more than a metaphor that masquerades as theoretical concept and … leads to a misleading picture of possible explanations in molecular biology. (Sarkar 1996,187)”[xvi]

I set out to answer the question of how the form of a plant, my bonsai specifically arises. The question is a general one about how the form of any organism arises and never fails to actualize? My exploration has been negative in that it has revealed to us that there is no genetic program, no blueprint, no genetic instructions encoded in the genome directing the development of the organism.  This leads us to another question then: why is the use of genetic information as the blueprint for development so widespread? In addition, what are the implications for biology and evolution if there is no genetic blueprint? These are interesting questions that I will explore in later essays.

 

References

[i] Wells J (2014). Membrane patterns carry ontogenetic information that is specified independently of DNA. BIO-Complexity 2014 (2):1–28

[ii] LOVE, ALAN C. “Explaining the Ontogeny of Form: Philosophical Issues.” A Companion to the Philosophy of Biology. Sarkar, Sahotra and Anya Plutynski (eds). Blackwell Publishing, 2008. Blackwell Reference Online. 09 March 2017

[iii] Franklin M. Harold . From morphogenes to morphogenesis. Microbiohgy (1995), 141,2765-2778

[iv] Tadanori Mammoto, Akiko Mammoto, Donald E. Ingber. Mechanobiology and Developmental Control. Annu. Rev. Cell Dev. Biol. 2013. 29:27–61

[v] Franklin M. Harold . From morphogenes to morphogenesis. Microbiohgy (1995), 141,2765-2778

[vi] Denis Noble. Genes and Causation. Phil. Trans. R. Soc. A (2008) 366, 3001–3015

[vii] Franklin M. Harold . From morphogenes to morphogenesis. Microbiohgy (1995), 141,2765-2778

[viii] Nenad Pavin, Iva M. Toli. Self-Organization and Forces in the Mitotic Spindle. Annu. Rev. Biophys. 2016. 45:279–98

[ix] Franklin M. Harold . From morphogenes to morphogenesis. Microbiohgy (1995), 141,2765-2778

[x] http://natureinstitute.org/pub/ic/ic11/genes.htm

[xi] Denis Noble. Genes and Causation. Phil. Trans. R. Soc. A (2008) 366, 3001–3015

[xii] Lenny Moss . A Kernel of Truth? On the Reality of the Genetic Program. Proceedings of the Biennial Meeting of the Philosophy of Science Association,Vol. 1992, Volume One: Contributed Papers (1992), pp. 335-348

[xiii] Paul E. Griffiths and Robin D. Knight. What Is the Developmentalist Challenge? Philosophy of Science, Vol.65, No. 2 (Jun., 1998), pp. 253-258

[xiv] LOVE, ALAN C. “Explaining the Ontogeny of Form: Philosophical Issues.” A Companion to the Philosophy of Biology. Sarkar, Sahotra and Anya Plutynski (eds). Blackwell Publishing, 2008. Blackwell Reference Online. 09 March 2017

[xv] Denis Noble. Genes and Causation. Phil. Trans. R. Soc. A (2008) 366, 3001–3015

[xvi] Paul E. Griffiths. Genetic Information: A Metaphor in Search of a Theory. Philosophy of Science, Vol. 68, No. 3 (Sep., 2001), pp. 394-412