One man's "magic" is another man's engineering. "Supernatural" is a null
word. (Heinlein 1973)

Success of the comparative method?

Chronobiology has made, and is still making, a tremendous progress at a neck-breaking speed. Forty years ago, there was something mystical and magical about mentioning a biological clock. Today, this is one of the best understood phenomena of biology at all levels of organization from organisms to molecules and back. In my opinion, the success is due to the comparative and integrative approach which was an integral part of this discipline from its outset. Organisms were observed in nature for centuries, hypotheses led to models early in this century, models led to standardized experimental protocols which were then used for study of hundreds of different organisms. The data started flowing in about protists, plants, fungi, invertebrate and vertebrate animals, and by 1960, the field knew what it was studying, what are the essential properties of the clocks, what are the probable adaptive functions of the clocks. A clear research goal and program were put in place which resulted in an explosion of knowledge about biological timing. Comparative studies described generalities and particularities. Integrative studies of a smaller subset of organisms led to a better understanding of molecular, cellular and organismal integration of circadian mechanisms. Everybody in the field felt a need to follow the advances in all areas of clocks research - molecular, cellular, developmental, neuroendocrine, physiological, behavioral, ecological, including studies of higher level phenomena such as photoperiodism, other circa-rhythms, and continuously consulted clocks. Although past few years have witnessed enormous successes of the molecular research, there is no apparent tendency to jump on the molecular bandwagon and forget everything else. For instance, the 1998 meeting of the Society for the Research of Biological Rhythms had more sessions on different aspects of evolution, function and comparative studies of organismal clocks then molecular sessions. At the 1999 International Congress on Chronobiology, the recurring theme was the "upward" direction of research, as the molecular knowledge was applied towards "building the organism". I ascribe the visible success of chronobiology to the adherence to the comparative and integrative approach to biology.

What would have happened if the clocks research did not do comparative work? Here is an example of an unsuccessful program: sleep research. The study of sleep was doomed from the outset as the pioneers were not biologists but physicians. Phenomenon of sleep was defined by the human EEG pattern, so a cursory glance at other animals led to the conclusion that mammals and birds sleep just like humans, and other animals do not sleep at all. As a result, nobody still knows what is sleep, what is wakefulness, what is the adaptive function of sleep, how did sleep evolve and what from. Now the sleep researchers are jumping on the bandwagon of molecular techniques. They are screening for differences in gene expression between sleeping and awake humans (or rats or mice), searching quite openly for the "genes for sleep". Every time they "fish out" a gene, it turns out to be Protein kinaze A, a dopamine receptor, or something similar with a general function in the brain. Don't they understand that sleep (like hibernation) is an emergent property of a multicellular brain? Unlike in the clock field, a single neuron does not carry the function - it does not sleep. Only whole (or halves of) brains can be asleep or awake. The sleep "mechanism" is not a molecular mechanism but a result of a particular pattern of neural connectivity and activity. Now, attracted by the successes of molecular chronobiology, sleep researchers are working on joining the two fields. In the process, I hope they see why chronobiology was so successful - because of the comparative/integrative approach. In fact, the new NIH/NSF guidelines for sleep research emphasize the need for comparative research of sleep both in a variety of mammals and in other organisms, including invertebrates (Turek 2000).

On the Aims and Methods of Biology

What is the object of study of the science of biology? The answer "Life" , although true, sounds too simple. To elaborate a little, biology is the study of living organisms: How are they built? How do they work? How do they behave? How do they interact with the environment? How do they evolve to be that way? and Why are there so many different kinds of organisms on Earth? The common theme of all these questions is the process of adaptation. Study of biology involves description and explanation of adaptations of organisms to their environments.

Let's for a moment go away from the hot issue of studying organisms and try to look at some of the same issues on a more emotionally neutral ground. I will now proceed to tell a story, really a thought experiment, that, in my opinion, can shed some light on the differences in possible approaches to studying anything.

The Science of Chairology.

An intergalactic spaceship, upon visiting Earth and collecting interesting specimens, distributes those specimens to the most eminent scientists of the Solar System. Each one of these scientists receives a shipment which includes a golden throne, a wooden baby highchair, an iron barstool, a wicker rocking-chair, a plastic Barbie-doll chair, a Styrofoam chair (a movie prop for filming saloon fights in Western films), and an aluminum office-chair on wheels. The question is: "What are these things?". The pre-eminent scientists, eager to win the prestigious Nebula Prize, promptly get to work.

The Honorable Venusian (HV) looks at the chairs, touches them, smells them, weighs them, takes some measurements, and concludes that these objects are beautiful, but too complex to be really comprehended. They are probably objects used in Earthlings' religious rituals, and might have sacred properties ascribed to them. Case closed, problem solved.

The Master Martian (MM) instructs his assistants to take small samples of materials that each object is made of. He then proceeds to grind, burn and analyze the samples, until he figures out all the elements and their relative proportions in each of the objects. He concludes that the objects are not members of a single class of objects, since each is composed of different materials in different proportions. He further concludes that some of the objects, those composed of single elements (gold, iron or aluminum) are not interesting, while the others, more complex ones (wood, wicker, plastic, styrofoam), are amenable to numerological analysis of proportions of elements which suggests that the objects contain coded information used in the communication between the Earthlings. Case closed, problem solved.

The Celebrated Plutonian (CP) gets really busy. At first, he makes all possible measurements of the intact chairs. Then, he starts taking the objects apart, trying to figure out how the objects were put together in the first place. He then takes parts of one chair off and replaces them with what he sees as equivalent parts of the other chairs, noting how the properties of the chairs change. He takes samples of materials and conducts a series of tests of mechanical properties of materials. In the end, he grinds the parts and figures out the chemical composition of all objects. He realizes that all the objects are made of different materials. However, they have some things in common. For instance, all but one object has a horizontal smooth flat surface, the exceptions being the rocking chair in which that surface is slanted, and the doll-chair in which that surface is small. That surface has at least one of its edges free, except for the highchair in which it is surrounded by vertical structures at all sides. That horizontal surface has at least one edge limited by a vertical surface, except in the barstool. The surface is more or less square, except in the barstool which is round. The surface is about two to three feet above the floor, except in the doll-chair, which is much lower. The surface can hold different loads - the throne can sustain enormous weights, the movie-prop and the doll-chair can support only very light objects. Also, the throne is very hard to move, the rocking chair is also quite cumbersome, while on the other end of the continuum, the office-chair can be easily rolled on the floor and the doll-chair can be carried in one's pocket. He points out that the most interesting aspect of the objects is the flat surface. As flat surfaces are good at keeping things from falling down on the floor, he concludes that the function of the chairs is to hold other objects which are put on them, but that the kinds of objects which are put on them are different for different chairs. Case closed, problem solved.

Intergalactic Captain Bobby (ICB) does pretty much everything the same as the Celebrated Plutonian. But, he is not satisfied with the answer. He wants to prove that his conclusions are right. He wants to know what kinds of objects are put on chairs, and why. Why are the chairs made of different materials and in different shapes and sizes? Why the chairs have those vertical surfaces? So, he gets on his spaceship and heads to Earth. At first, he puts his UFO in orbit and tunes in to the local television station. As soon as he switched his monitor on, he saw what he wanted - a chair. On the screen, a human was holding a chair by its vertical element and pointing the chair's legs towards an enormous orange-and-black cat which was sitting on top of a conical structure inside a large round cage. A-ha! So, the chair is used as a defense mechanism against large predators! He switched to another channel. There, an unshaven human wearing a large hat was hitting another human on the head using a chair! Oops! The chair is here used in male-male competition! Another channel. PBS. Very interesting. A human explains step-by-step how a chair is made out of wood. Next channel. A monkey is sitting in a small chair, his head covered with wires, his eyes looking at a monitor. Ha! A chair is a piece of laboratory equipment! After several months of studying humans, both on TV and on the ground, ICB finally concludes that the main function of a chair is for the humans to sit on them. The different sizes and shapes reflect different needs of humans in different human environments, as well as esthetic preferences of humans which change over time. Case closed, problem solved.

Who learned the most? Whose conclusions were most correct? Whose answer is most complete? Finally: Who got the Nebula Prize? Well, Master Martian, of course! The Nebula committee members are all from Mars!

Still, there are some points to consider before we turn to actual organisms. How did the differences in method lead to different conclusions? Why did ICB's method turn out to be the most successful? Looking at a whole object is necessary, but insufficient for either description or explanation of that object. Looking at the chemistry of the object is necessary but insufficient for either description or explanation of the object. Looking at the object as a whole, its chemistry, its parts and interactions between the parts is necessary and sufficient for the description of the object. However, it is necessary but insufficient for explanation of the object. Explanation needs three more aspects of analysis of the object: the process by which it is built, the way it interacts with its normal environment, and its history. Without these, the explanation is incomplete and likely wrong, and the description is irrelevant. Even apparently static objects are not really static - they change and their environment changes, so the study of a "snapshot" of an object in isolation is a method of limited value.

One more point needs to be made here. It is not necessary for a single person to tackle a large problem by him/herself. The four scientists could have divided the job. HV does the work on whole chairs, CP breaks them apart, MM studies the chemistry, and ICB goes to the field and comes back with the organizing theory of their joint research. As long as they all read each others' papers, the discipline of Chairology will proceed faster and their conclusions will less likely be erroneous than if each works in isolation.


Methods in Science: Holism, Reductionism, Mechanism.

I don't think I really need to explain in great detail how the "chair" story corresponds to the various approaches of biologists on Earth. HV stands for Holist Vitalist, MM for Molecular Madman, CP is a Classical Physiologist, and ICB is an Integrative Comparative Biologist. The poverty of the holistic method is so obvious that philosophers of science rarely even waste their time on analyzing it (Brandon 1996, Ch.11). I won't either. The distinction between the other three approaches is still quite contentious. All three are brands of reductionism, as the term is usually used. MM is a "philosophical reductionist" (Rose 1998), " strong reductionist" (Brandon 1996, Ch.11), or "vulgar reductionist" (hallway vernacular). The other two guys are "methodological reductionists" (Rose 1998) or "mechanists" (Brandon 1996). The distinction between the two brands of reductionism lies in the differences between its practitioners in the beliefs about the way life works and the way science is done.

The vulgar reductionist is influenced by the philosophy of physics. Physics is in a search for universal laws. Supposedly, smaller the particles one studies, closer to the universals one gets. A vulgar reductionist has a gut feeling that biology is all "mushy" and that the goals of modern biologists is to discover universal laws of biology. Guided by physics, the biologist needs to look for these laws at the lowest possible level: the biological molecules today, perhaps atoms tomorrow. Description of molecules is an explanation of organisms. The level of molecules is a priori set as the single basic level of explanation in biology (Brandon 1996, Ch.11), which is exactly the same mistake as the holistic view of the non-divisible higher levels.

The methodological reductionist realizes that a living organism is a very complex system, which, as a whole, is not amenable to study. Thus, the problem needs to be broken down into chewable chunks. There is more than one way to break down a problem. One can break the system into its constituent physical parts, study the property of parts in isolation, study the properties of the system when the parts are removed, reassemble the parts into a whole again and infer the functions of the parts, their interactions, and the ways they are integrated into a functional whole. The other way to break apart a problem is to separately study different conceptual aspects of the problem. A large question is broken into a number of smaller answerable questions. The small answers are put together and tested against the whole system again. The two methods are complementary and they are both valid and useful. The organism, being a complex, hierarchical and dynamic system needs explanations at several different levels corresponding to the levels of organization of the organism. The interactions between levels needs to be explained. It also needs to be explained in terms of change over time. And it needs to be explained in terms of regularities of the system which may or may not be mathematizible. Finally, the organism can be properly explained only in reference to other organisms.

The main strength of this approach is that there is no a priori statement of levels at which a mechanism needs to be studied - it is the goal of research to discover the proper levels of explanation of mechanisms on a case by case basis.

Now lets loook at the question of competition between Molecular Biology and Organismal Biology. How do the two disciplines map onto the taxonomy of methodological approaches. If we agree that methodological reductionism is better than vulgar reductionism which is better than holism, is, perhaps, one or the other discipline potentially more useful because it adopts a better research approach?

Within Biology, Molecular Biology studies the role of macromolecules, primarily DNA, in development, function, behavior and evolution of organisms. Organismal Biology studies the functioning of whole organisms, as well as the ability of constituent parts to coordinate their activities in order to allow the whole organism to adaptively react to the challenges from the environment. Are these approaches mutually exclusive?

In my humble opinion, Molecular Biology and Organismal Biology do not belong in the same classification scheme. Organismal Biology is defined by the kinds of questions it is asking. Molecular Biology is a collection of laboratory techniques. These techniques can be used to address a number of different kinds of questions, which means that Molecular Biology is not its own discipline, but, at least potentially, part of methodology of several different branches of biology which are concerned with quite different questions. These molecular techniques are very powerful, and extremely useful in studying various problems of biology. All biological disciplines are, quite rightfully, more than eager to incorporate molecular techniques into their arsenals. In a way, molecular biology has had, and still does exert a large influence on integrating various disciplines into a more unified Biology.

But why is this question of competition between molecular and organismal biology even raised? That is because molecular biology, from its inception, has been historically identified with a discipline of Genetics, a method of vulgar reductionism (later the miraculous claims of the expensive Human Genome Project), and a world view which can be best termed "genocentrism". Genocentrism is a claim that all aspects of a living organism can be explained by the sequences of nucleotides in its genes. In other words, all phenotypic traits can be traced directly to the genotype. There is a one-to-one mapping of genotype onto phenotype. Is this claim true? Well, the geneticists are the first to say No. Almost a century of research has shown that most genes code for proteins which are involved in more than one process (epistasis) and that many proteins are involved in execution of any single process (pleiotropy), leading to a many-to-many mapping of genotype to phenotype. However, the primacy of genes, one or many, in determination of all aspects of the organism is rarely contested within genetics. The possibility that genes are not the only sources of biological information is, by them, considered a heresy. Are they correct about this?

What is a gene?

In classical genetics, after Mendel and before Watson and Crick, gene was a unit of hereditary information. It was a theoretical term, with no knowledge about its correspondence to a real physical entity. After Watson and Crick, gene started being identified with a string of nucleotides of DNA. This string was supposed to contain hereditary information, to control the process of development, and to control all aspects of function of the organism. There was a shift from a view of information which is passively transmitted, to a new "discourse of gene action" (Keller 1995) with genes being active agents. They are not just existing, they are doing something, too. Moreover, they are doing everything, they are in control, the masters of life. Where did this idea come from? From the physicist Erwin Schroedinger. In 1944 he published a little book "What Is Life?". According to their own accounts, reading this book prompted Watson, Crick and many others to search for the secrets of heredity. According to the book, a gene is a "law-code and executive power-...architects plan and builder's craft - in one" (1944, p:23). This idea led to a very powerful research program resulting in the elucidation of many aspects of biological function at the molecular level, as well as to development of powerful laboratory techniques. However, this view left the cell, the embryo, the organism, and the environment out of the picture. But, can they be ignored? Is the gene-control metaphor correct?

As Richard Lewontin put it succinctly,

In other words, minimal unit of hereditary information is not the genome, but a totipotent cell - a cell capable, given optimal environment, of developing into a new organism. This cell is (usually) the smallest package necessary for an organism to pass through the bottleneck between the parent stage and offspring stage of the reproductive continuum. A life cycle of the organism is the succession of stages between two bottlenecks (although some barnacles parasitizing on crabs actually go through another single-cell bottleneck somewhere in the middle as they need to get small to invade the host). In a unicellular organism, the totipotent cell is every cell of the organism, both in its one-cell stage, and in its two-cell stage. In a colonial organism, every cell is a unit of hereditary information. In a more integrated organism, like Man-O'-War, the cell/organism adopting a role of the gamete is the unit. In a multicellular organism, the unit is the egg-cell which, in some cases, needs to be fertilized in order to initiate the embryonic development.

Genes and heredity.

What are the usual arguments for the primacy of genes in transmission of hereditary information (Sterelny and Griffiths 1999, Chapter 5)? A) They are directly replicated. B) All other developmental factors are ultimately dependent on genes. C) Variation in genes causes variation in their effects. D) Genes are reliably remade in every generation. Are these arguments valid? Here are some answers from the Developmental Systems Theory (Oyama 1985, Griffiths and Gray 1994):

A) The genes are copied accurately, but at a cost of a mediated replication process which is at least as complicated as epigenetic inheritance mechanisms. B) Perhaps it is true that no other developmental mechanisms are possible without the genes, but also, there can be no genes without proteins and cell membranes. Just as all cellular functions have genes among their causes, so all gene regulation events have cellular events among their causes. C) If all the background conditions are kept equal, an allelic substitution may result in a change of a trait. However, if the genetic background is kept equal, different cellular and extracellular conditions will also result in a change of a trait. So, instead of a "gene for" a trait, we might talk about a "temperature for" a trait. D) DNA replication is a high-fidelity process. The sequences of nucleotides are copied very accurately. However, the genes' relational properties are much less accurately copied (in crossing-over, deletions, inversions, etc.). Some epigenetic patterns are also copied very reliably. The DNA methylation pattern is accurately replicated by a special methylation copying system. All the cellular membranes are formed from a template from the maternal cell. Polarity of the biogenic magnetite in magnetotactic bacteria is determined by a maternally transmitted seed-particle.

But why stop at the cell? Organisms also live in environments. During embryonic development, phenotypes can be determined by maternal hormones. Metamorphosis may depend on an environmental trigger. An insect will oviposit on the same kind of plant on which she grew up. Sex of a reptile is determined by temperature, which is, in turn, dependent on mother's behavioral choice of nest site. A male songbird which did not learn the courtship song from his father is not a complete bird: it is devoid of crucial hereditary information needed for reproduction, so it is an informational, as well as evolutionary dead end. A shiny, good-looking male sparrow will be chosen by the female and will reproduce, but, he does not have a "gene for" good looks. He is healthy because his father spent much time cleaning the nest and the chicks against parasites, and the son, who has presumably learned his father's hygienic habits, will do the same for his offspring. Pup-grooming behavior of the mother rat influences the extent of stress responses (including gene expression in brain regions that regulate stress reactivity) in her pups, as well as their subsequent pup-grooming behavior (Francis et al. 1999). These are the cases of entirely phenotypic inheritance.

At the next level, the social organization can be transmitted non-genetically, too. For instance, in fire-ants, there are two types of social organization: single-queen and multiple queen colonies. There is a constant gene-flow between the two types, so these are not two populations in a process of sympatric speciation, and there are no genetic differences between the two. However, there are differences in allelic distributions. These differences are not effected by genetic mechanisms, but by pheromonaly guided selective murder of inappropriate types of queens by workers (in a polygynous colony) or the queen (in monogynous colony). All the differences between development, morphology, physiology and behavior of the queens of two different types of colony are the result of behavior, mediated by pheromones. To close the feedback loop here, the levels (or kinds) of pheromones are determined by allelic combinations of the same genes in both types of colonies.

Taking into account all of the aforementioned accounts of non-genetic heredity, even the notion of the totipotent cell as the minimal unit of hereditary information is insufficient. The DNA, the proteins, the membranes, the cells, the organisms, and the environments ALL need to be accurately replicated from one generation to the next (Griffiths and Gray 1994). The whole life-cycle is a unit of hereditary information (Oyama 1985), and there are no bottlenecks, as the transmission of information is continuous and uninterrupted since the origin of life on Earth.



Constructing an organism: a hierarchical view of life

DNA is not isolated from its immediate environment. It is affected by it, and in turn, it affects it (Rose 1998). Proteins manipulate DNA, squeeze the information out of it, use that information to make other proteins which in turn further affect the DNA. The proteins themselves are in a continuous dynamic relationship with their own environment which include other proteins, DNA, cell organelles and membranes, small molecules. The proteins may exit the cell and enter another cell, or, they might have to deal with another kind of molecule which entered the cell from outside. The cell itself is best defined by its boundary - the cell membrane. This is where the inside and outside environments of the cell meet and exchange information. In the healthy cell, the correspondence of the inside and outside is equivalent as "[I]nternum and externum have equal roles in the determination of cellular behavior" (Lintilhac 1999).

As we go up the levels, the story repeats - tissues are affected by their environments as much as they affect other tissues. Same goes for organs, organ systems, organisms in their outside environment, populations in a community. At each level, there is an equivalence between "upward" and "downward" interactions, which determines the present state and behavior of that particular level of organization.


Downward Causation.

However, there is one sense in which these interactions are not equivalent. That is the sense of constraints. The lower level is always constrained by the higher one. An animal might be potentially capable of a broad range of responses, but the environment dictates which of these responses are actually used. Intestine may be capable of normal digestion in a very broad range of temperatures, but it will never encounter most of these temperatures as the whole organism will keep the body temperature within a much narrower range, and, even if the organism goes to a thermal extreme (e.g. hibernation), it is likely to first "switch off" digestion by a neuroendocrine signal. Thus, the gut NEVER gets to show off its amazing capability (except in the laboratory, perhaps). A cell has a potential for many ways of differentiating and functioning, far more than actually happens, as the development of the organism restricts what cells of that particular organism can and cannot do. Genome of an organism has almost endless numbers of patterns of expression it may assume in different cells. In reality, the expression patterns are highly constrained by the activity of proteins in those cells. Atoms of different elements have a large variety of different physicochemical properties. Only some of these will be actually used by the atoms incorporated in the large biomolecules. The activity of atoms will be constrained by the structure of the macromolecule and its environment. Even the properties of subatomic particles are constrained by the atoms. The fundamental laws of physics allow the subatomic particles to behave in a variety of ways. All these ways are possible, and all are in compliance with laws of physics, but they are not all actually expressed - they are constrained by the behavior of the next higher level. And, the behavior of that next higher level - the atoms - is not explainable by laws of physics. It is in compliance with the laws, but cannot be predicted from these laws.

Contingent Explanation

The behavior of atoms does not have laws. It obeys fundamental laws of physics, but it is contingent on the detailed specifications of this particular Universe. In another Universe, the fundamental laws of physics will probably be the same (or will they?), but we cannot predict the actual behaviors of particles. The same argument can be brought up at all levels (Brandon 1998). Behavior of cells is in compliance with laws of physics, with properties of atoms in this Universe, and with properties of macromolecules on Earth, but is not lawful itself, and cannot be explained by the lower levels. The behavior of cells is contingent on the history of organisms on this planet. Another planet will probably have different cellular properties, if there were cells at all, contingent on the history of life on that planet, and in compliance with the behavior of particles in this Universe.

What does it all mean for the methodology of biological investigation? The events at one level cannot be explained by the "rules" of the next lower level, but can be explained by the constraints imposed by the next higher level. To put it bluntly, genotype can be explained by phenotype and not the other way around. Structure of hemoglobin cannot explain why I breathe, but the fact that I do breathe explains the presence and the properties of hemoglobin in my erythrocytes. The entire range of properties of a system can be elucidated, but its real function can be understood only by studying which of the potential properties become actual in nature. A bird feather has a potential to be used as a writing tool, but only by studying actual birds in real environments we will understand that this is not its actual function in a bird. Study at one level determines the possible, the study at the next higher level determines the actual. Only by studying both we can really understand a biological function.


Running with the organism: a dynamic view of life

Organism is never the same as it was a second before. It is in a continual flux. Its life cycle is one long and regular process. Onto those changes one can add shorter regular fluctuations associated with annual and daily cycles, and even shorter changes as the organism deals with its environment on a moment-by-moment basis (Rose 1998, Mrosovsky 1990). As a single cell develops into an embryo and the embryo into an adult, and the adult gets into and out of reproductive state, ages and dies, which stage is typical? At which moment should we take a picture of that organism, or stuff it for a museum? When are we supposed to take the tissue to freeze and put on the microscope slide? At which point in time should we look at the patterns of gene expression? Is a mature adult more of an organism than a fetus, or zygote? Does an adult contain more information than an egg?

A genocentric answer is that it does not matter since there is one property of the organism which never changes and that is the sequence of its genome. The genome is the essence of the organism. It is a blueprint for building an organism and a program which directs the process of building the organism. All the relevant information about the development, morphology, physiology and behavior of the organism is written in the DNA. DNA codes for all traits and controls their development. Thus, genocentrism ignores time. It is static, rather than dynamic. It is content with a "snapshot" of the organism. It is focused on the "essence" of the organism - the description IS the explanation.


What does the gene code for?

The linear order of nucleotides in a functional segment of the DNA codes for the order of nucleotides of the primary RNA transcript. In prokaryotes this transcript further codes for the primary structure of proteins (linear sequence of amino acids), so in a sense, DNA indirectly codes for protein. In eukaryotes, the process of coding breaks down earlier, as the primary transcript is edited and its introns removed. At the ribosome, the protein might get further edited. The secondary, tertiary and quaternary structure of the protein is determined by the intrinsic properties of the protein, by protein-protein interactions, and by the cellular environment. It is the tertiary structure of the protein which gives it a functionality, or a role, in the cellular metabolism. Can the gene code for something more, like the phenotypic trait which is influenced by the protein? Yes or No, depending on one's definition of "coding". No, if one insists there would be a one-to-one correspondence between every piece of the code and every piece of the final message i.e., if "code" equals "template". Yes, if one agrees that a code can induce a result without precise mapping. Commander-in-Chief can send a single word as a coded message to his generals in the field, and they will understand the code and initiate a whole set of complex military maneuvers. However, the generals need not only to be able to read the code, but also to interpret it correctly, which means that the whole war action needs to be planned in advance. A gene codes for a trait if the cell and the organism "know" what the code means in every particular situation - the whole plan is not encrypted in the code, it was there all along, and the code acted only as a trigger.

What is genetic information?

Sequence of nucleotides, to some extent, contains the information about the sequence of amino acids in the protein. Also, protein contains information about the gene sequence which codes for it. However, in a different sense, information is unidirectional, as only the gene contains imperative information - instruction how to build the protein. The protein does not contain instructions for building a gene (Godfrey-Smith 1999).
In a constant environmental background, genes carry information about phenotypic traits. Likewise, in a constant genetic background, environments contain information about the phenotypes. And phenotypes contain information about environmental conditions.

What do genes cause?

What is a gene for? In the statistical sense, a gene is gene "for" a trait if it correlates with that trait. In a causal sense, a gene is gene "for" a trait if its transcription starts a cascade of events which results in that trait. In a teleonomic sense, a gene is gene "for" a trait if it has been maintained by natural selection because of its association with that trait (Godfrey-Smith 1999). In all three senses, one can also talk about environments "for", or epigenetic transmission mechanisms "for" a trait.


Do genes control development (and physiology and behavior)?

"To 'control' a process means to exercise a directing or restraining influence over it" (Nijhout 1990). A product of a gene may be required for a biological event. The expression of the gene is triggered by a specific stimulus, e.g., an ion, or a protein which is a product of a regulatory gene which in turn is triggered by another stimulus and so on. The pathway is endless and involves genetic, as well as physical and chemical events. Lack of any one of these factors will stop the process. When a protein is needed, its production is activated by a signal from the environment, not by the gene itself. When a non-protein is needed, the gene products cooperate with other cell components to make or import that substance. The genes do not provide the instructions for the process, but "aid in supplying the material basis for development"(Nijhout 1990).

Gene expression during development is often sequential. Does that mean that genes contain a developmental 'program'? A program implies that the gene product is necessary and sufficient for the occurrence of the process and is not itself provoked by the process (Nijhout 1990). Also, it requires that the genes contain information about the temporal sequence of events. However, the expression of the genes is activated by the temporal and spatial interactions between genes and their cellular environments. The pattern of gene expression is not a program, it is both a consequence and the contributor to development.

To quote Nijhout (1990) again:

Prevalence of the genocentric view

It would be easy to get carried away and write a whole book about the omnipresence of genetic metaphors in media, movies, literature, popular science reporting, even scientific papers. Such books have been written already (e.g., Keller 1995, Nelkin and Lindee 1995, Hubbard and Wald 1993). Instead, I will try to just briefly present some main ideas about the feedback between science and society, and particularly about the effects the lay understanding of science can have on the scientific practice.

From science to society.

What are the facts? Again and again and again - what are the FACTS? Shun wishful thinking, ignore divine revelation, forget what "the stars foretell", avoid opinion, care not what the neighbors think, never mind the unguessable "verdict of history" - what are the facts, and to how many decimal places? You pilot always into an unknown future; facts are your single clue. Get the facts! (Heinlein 1973)

Life is messy. We are alive. Ergo: we are messy. We get sick, we die. Nature is unpredictable. That is scary. Making sense of the world, taking it apart and storing the parts in neatly labeled little drawers, is almost necessary for our mental health. This is such a great need that we will uncritically buy any and every kind of explanatory scheme about the world that seems to have at least some internal logic and some, even tenuous, connection to reality. If there is nothing better, we will believe in astrology, supernatural beings, parapsychology,... anything that helps us make sense of the world. Some knowledge is better than none. We want to know because we fear the unknown, because we are endlessly curious, and because we understand that knowledge is power. Only if we understand a thing or process we can ever hope to manipulate it to our purposes, the ultimate purpose being elimination of one's personal death.

During the past few centuries, one method of acquiring reliable knowledge, with concomitant ability to manipulate the world, became most prominent. That is the method of science. Science earned its predominant respect due to its successes - science works. It works much better than any alternative method. Science takes credit for all the technological innovations which made our lives so much safer than at any previous time. Science is giving us more and more control over previously uncontrollable aspects of nature, including our own health.

The primacy of scientific knowledge does not mean, however, that most people fully understand the intricacies of nature, or fine points of scientific method. It is only the practical results which directly concern most humans. Just as the theologians are the masters of religious knowledge, so are the scientists masters of scientific knowledge. Whoever is outside of the inner privileged circle has to take the words of the masters on faith. However, there is a subtle difference between religion and science in one important respect. Theologians and priests are the ones who synthesize and popularize religious knowledge. In science, there is an intermediary between the working scientists and the audience - the media. It is the media which takes results of scientific research, turns them into stories and metaphors, and feeds those to the general population. It is the job of a good journalist to take complexity of scientific understanding and make it simple. A good metaphor is worth a thousand words.

The origin of the gene metaphor.

Many biologists would agree with the description of biological systems I outlined in the previous section. It makes sense and it is compatible with the existing data. Why is such a view of life not more widely known and accepted? What is it about the gene-control metaphor that is so seductive to the majority of human beings? Is there anybody to blame for its prevalence? Where did this metaphor come from in the first place?

Early twentieth century geneticists were not naive about role of genes in development and evolution. Muller, Goldschmidt and other pioneers were fully aware of the important role of the cell and the environment in heredity and evolution. Why did that understanding disappear? One reason is the fact that the material basis of heredity, including the structure of the DNA molecule, was not discovered by biologists. After the W.W.II and the appearance of influential Schroedinger's little book (1944), it was chemists, biochemists, and even physicists, who decided to tackle the task of figuring out the molecular counterpart of the concept of the gene. Without a background in biology, and rooted in the reductionist spirit of their own disciplines, they forgot the organism. Being in the midst of an information revolution, remembering the wartime secret codes, seeing the invention of television and first computers, they thought about heredity in terms of information. They sought a molecule which can contain coded information. Under Schroedinger's influence, they assumed that such a molecule will also be capable of executing the transmission of the code. They forgot that code is a mechanical way of conveying a meaningful message, and that transmission of a message requires a writer and a reader. Who are the writer and the reader? If asked, they might have answered that the parent is the writer and the offspring is the reader. The embryo was gone. Embryology was dead for a couple of decades, until it redefined itself as the study of the execution of the genetic program (Keller 1995).

When the code was cracked and Watson and Crick received their Nobels, the molecular revolution got started. The main proponents were quite vocal with their irresponsible pronouncements. Watson said that apart from the atoms everything else is social science. The existence of the code and the program meant that biology had laws reducible to physics. The Dream of the Final Theory of Everything can now include Life.

The Goddess of DNA.

Evolutionary biology did not miss this message. First George Williams (1966), later Richard Dawkins, (1976, 1982, 1986, 1995) and more recently philosopher Daniel Dennett (1995), promoted the view that we are just robots that genes use to make copies of themselves. A hen is a gene's way of making another gene - forget the egg! Much of the genocentric evolutionary biology relies on the computer models and games of evolution. In these games, very simple rules of mutation, copying and selection result in speedy appearance of quite amazing diversity of cyberorganisms. But, there is no development in these games. The fact that the evolution on the computer screen appears to have the same end-results as the organic evolution does not mean that the organic evolution works in exactly the same way. Languages evolve in apparently the same way. Given the three basic rules (variation, copying, selection) any system would evolve, but that ignores the fact that each system will also have its own modifications of the rules, additional rules, and inherent constraints. If it looks the same, it is not necessarily the same. If an engineer makes a robot that looks like an insect and utilizes same principles of sensory-motor integration like an insect, is that a real insect? Well, it looks like one and it behaves like one, but it has a battery pack, aluminum body, and pneumatic legs. It cannot reproduce and it cannot change "on its feet" without stopping and reassembling parts.

Evolutionary genocentrism, by ignoring all forces but natural selection, expects perfection in adaptation, and cannot explain diversity. To use Gould's metaphor, if one replays the tape of Earth's history a million times, Daniel Dennett's writings predict that all million times there will be intelligent humans on this planet and that there will be a Daniel Dennett writing a book called "Darwin's Dangerous Idea". So, this is the best of all possible worlds by virtue of being the only possible world. Its design is perfect. If God had a really big computer and played an evolution game on it, this is exactly the kind of world that would arise every time he played.

Genes are immortal (soul) and everything else is transient (body as a receptacle and vehicle for the soul). What a fantastically easy replacement for God in the age of wavering religious feelings! Through our genes we acquire immortality. If in the beginning there was a Word, it was written in genetic code, and each one of us carries a copy of it in each one of our cells. By deciphering the code (Human Genome Project) we will finally Know who we really are and what is our purpose in the world. Perhaps Dennett's Dangerous Idea and Behe's Black Box are not incompatible!

From society to science.

The early successes of molecular genetics brought about the genocentric view of life. It obviously deeply resonated with the general population. The effects of this view can be felt in the courtroom, in government, in medicine, agriculture, psychology, environmental protection, and almost every other aspect of society. How did it affect the practice of science (particularly biology) itself?

Molecular biology is where all the excitement seems to be. Government is pouring money into it. Nobel prizes are given for its results. If the genes and environments both influence the appearance of a disease, manipulating the gene is easy and profitable, while eradicating pollution or poverty is hard and drains money (Gannett 1999). Private business is raising the stakes, too. Molecular biology labs look more and more like factories for production of data and production of Ph.D. technicians for the biotechnology industry, where mastery of technique is paramount over scientific curiosity and creativity. It sometimes seems like the whole of biology has been reduced to medicine, as the questions directly affecting human health have pushed all other questions out of limelight and money. Plants and animals are just not interesting any more.

The sense that 'message is the medium' and that the sequence of nucleotides is a message to us if we just learn how to read it spawned a whole new discipline - genomics. At least the choice of the word is honest. It does not end in -ology. Rather, it sounds like a brand of economics. Sequencing the human genome and a few other genomes of model organisms ("in vitro animals") is a huge endeavor. Methodologically, however, it is a non-manipulative descriptive work - not an experiment. Cataloguing all the species of organisms on Earth is one such endeavor, but nobody claims (although one might conceivably do) that only when all are catalogued will some pattern be revealed which will tell us about the meaning of life. Genomics claims exactly that.

So far, a gloomy picture. But is it really so bad? I suggest it is not. Advances in molecular techniques and the increasing number of people in the field resulted in an enormous amount of research being done at an astonishing pace. And, as the geneticists do their work, they bump into problems with their genocentric hypotheses. As they solve those problems, they become more and more sophisticated about molecular mechanisms. It is the geneticists who discovered and study epigenetic processes like gene imprinting and DNA methylation. They discovered introns, reading frame-shifts, protein folding. They are increasingly aware of the organism and are silently, but for PR purposes still not loudly, abandoning the genocentric view. Research is slowly shifting from DNA sequences to the study of spatial and temporal patterns of gene expression in various cells and tissues, to the study of proteins, and cascades of enzymatic reactions.

As much as the HGP spokesmen get media coverage, the small army of biologists is actively working on integration of molecular insights into many other areas of biology, including embryology, physiology, ethology, ecology and evolution. The result of this effort is not a general molecularization of biology. Quite opposite is happening: By adding another level of investigation, each of these disciplines becomes more integrative. Molecular data are becoming bridges between quite disparate disciplines. Molecular techniques have become a glue which holds together various parts of biology tighter than ever before. Biologists, trained in biology proper and not biotechnology or medicine, will never abandon the hierarchical and dynamic view of life. They were just handed the tools by which they can, for the first time, get a "handle" on the complex processes of development, physiology and behavior. Genes are the technically most convenient point of entry into the system, as well as most reliable markers of differences between organisms, so both the integrative and the comparative method have profited from inclusion of molecular techniques into their armaments.

The hype of the HGP and the race to perform the whole sequencing job as well and as quickly as possible led to fast improvements in the techniques. These techniques can be used for other types of research, too, as well as for sequencing genomes of other species - mouse and fruitfly today, thousands of species tomorrow (Kitcher 1999). So, I say, pour the money on genomics. Make them finish the job as fast as possible. Sooner they are done, sooner we can allocate the resources to more meaningful research (before organismal biologists die out and there is nobody left to teach students how life works).

I am willing to bet that molecular geneticists, the same ones who now proclaim Organismal Biology dead, will, in a few years, and upon their discovery of the organism, announce with great fanfare the dawn of a new paradigm in biology - organismal biology. What new paradigm? After a couple of centuries of health and prosperity, a temporary delusion will do no harm. The old mother Organismal Biology will lovingly take her rebellious molecular children back into her fold.


So, Is Darwinian Method Still Applicable Today?

So far, I have attempted to describe Darwin's methodology, to test it against the field of Chronobiology, and to draw conclusions about it's possible usefulness in today's biology. In the previous sections I have concluded that the quantity and kind of information available to the biologists will differently affect the correctness of his or her hypotheses dependent on the scope the theory is trying to encompass. A grand theory of everything depends on a wealth of observational information from many organisms (comparative method), as well as from many different areas of study (consilience), but is not dependent on a wealth of experimental data on proximate mechanisms. On the other hand, a narrowly focused theory is highly dependent on the quantity and quality of detailed information about the underlying mechanisms (integrative approach). Quality data are those which have been shown to be generally applicable to many organisms, so only facts gleaned from comparative work are useful for building a theory.

Darwinian method has the potential to prevent a number of mistakes that today's biologists sometimes make. First, application of integrative and comparative method prevents one from stating unwarranted generalizations from data obtained from experiments on a single strain of a single species all reared and kept in the same environmental conditions of the lab. A mechanism elucidated in fruitflies is not automatically the law for all animals, unless and until it has been shown that the same mechanism operates in a wide variety of organisms. Tractable models are excellent starting points for research, but the results become interesting and important only when they are applied to the study of similarities and differences in many other organisms.

Second, Darwinian method prevents one from remaining indefinitely at one level of organization. Comparison of organisms which are similar at one level (e.g., same genes) but differ at another (e.g., different phenotypic traits) will inevitably invite the question of what is happening at intermediate levels to account for such differences. The researcher gains appreciation for the hierarchical organization of life and will have to abandon genocentric sentiments. The same process of discovery will lead one to understand the dynamic structure of life and uselessness of study of static entities like frozen cells or nucleotide sequences.

However, Darwinian methodology requires a prepared mind. A feed-forward process of discovery is dependent on the observer's received knowledge and understanding of the world. Darwin KNEW his natural history. When he went into the field he knew what he was looking at and also what to look for. A lab scientist has to know what to look for and what experiments to do. A theoretical paper has to be read critically in light of one's knowledge about life. In order to do comparative work, one needs to know what kinds of organisms exist out there, what each one of them does, and how does it differ from the others in order to choose the right species to study in more detail. In order to form a theory, one has to be familiar with a large body of literature on many aspects of biology.

In Darwin's day, natural history was a hobby. Everybody went collecting or bird-watching on weekends. Everybody read Natural History books and travelogues from distant lands. General audience was familiar with almost every example Darwin put forward in his many books. Today, biology courses in the schools teach photosynthesis, Krebs cycle, DNA transcription, population cycles, and many other extremely valuable facts about life, but no natural history, and this at the age when so many people live in cities and have no first-hand contact with real nature. Animals are Disneyfied and images of nature rendered sterile. Nature shows provide a great deal of information but in a way which removes and alienates viewers from nature. As a result, today's biologists know less natural history than factory workers in 19th century England. If writing today, Darwin would have much trouble providing his readers with examples they were familiar with, and as a result would have more trouble persuading everybody in correctness of his theories. I do not pretend to have a recipe to alleviate this situation, but I feel that if general population was in some way made to learn more natural history first-hand, than the new practitioners of biology would naturally adopt Darwinian method, leading to better science and better understanding of the world.


References

Abrami, G. 1972. Correlations between lunar phases and rhythmicities in plant growth ender field conditions. Can.J.Bot. 50:2157-2166.

Adkins-Regan, E., Ottinger, M.A. and Park, J. 1995. Maternal transfer of estradiol to egg yolks alters sexual differentiation of avian offspring. J.Exper.Zool. 271:466-470.

Arrhenius, S. 1898. Die Einwirkung kosmicher Einflusse auf physiologische Verhaltnisse. Skandinavisches Archiv fur Physiologie, Vol. VIII.

Aschoff, J. 1964. ed. Circadian Clocks.Proceedings of the Feldafing Summer School, 7-18 September 1964. Amsterdam: North Holland.

Aschoff, J. 1965. Circadian Rhythms in Man. Science, 148:1427-32.

Aschoff, J. 1969. Desynchronization and Resynchronization of Human Rhythms. Aerospace Medicine, Vol 40. pp. 844-9.

Aschoff, J. 1998. Circadian parameters as individual characteristics. J.Biol.Rhythms 13:123-131.

Baker, J.R. 1937. Light and Breeding Seasons. Nature 141:414.

Baker, J.R. 1938a The relation between latitude and breeding seasons in birds. Proc..Zool.Soc., Ser.A.39:557-582.

Baker, J.R. 1938b The evolution of breeding seasons. In: Evolution: Essays on aspects of

evolutionary biology, G.R. de Beer, ed. Oxford.

Bennett, M.F. 1974. Living Clocks in the Animal World. Charles C Thomas - Publisher.

Berthold, P. 1993. Bird Migration: A General Survey. Oxford University Press.

Bonner, J.T. 1993. Life Cycles. Princeton University Press.

Bornemisza, S.T., 1955. The Unified System Concept of Nature. Vantage Press.

Brandon, R.N. 1996 Concepts and Methods in Evolutionary Biology. Cambridge University Press, Cambridge, UK.

Brandon, R.N. 1998. "Does Biology Have Laws? The Experimental Evidence" PSA?

Brigham, M.R., Gutsell, R.C.A., Wiacek, R.S. and Geiser, F. 1999. Foraging behavior in relation to the lunar cycle by Australian Owlet-nightjars Aegotheles cristatus. Emu 99:253-261.

Bronson, F.H. and Heideman, P.D. 1992. Lack of reproductive photoresponsiveness and correlative failure to respond to melatonin in a tropical rodent, the cane mouse. Biol.Reprod. 46:246-250.

Bronson, F.H. and Heideman, P.D. 1994. Seasonal regulation of reproduction in mammals. In: The physiology of reproduction, Knobil, E. and Neill, J.D. eds. Raven Press, New York.

Brooks, D.R. and McLellan, D.A., 1991. Phylogeny, Ecology, and Behavior: A Research Program in Comparative Biology. The University of Chicago Press.

Bunning, E. 1936. Die endogene Tagersrhythmik als Grundlage der photoperiodischen Reaktion.

Ber.Btsch.Bot.Ges. 54:590-607.

Bunning, E. 1956. Endogenous Rhythms in Plants. Ann.Rew.Plant Physiol. 7-1956-71.

Bunning, E. 1958. Cellular Clocks. Nature. 181:1958-1169.

Bunning, E. 1973. The Physiological Clock. New York:Springer-Verlag.

Campbell, J. 1988. Winston Churchill's Afternoon Nap: a Wide Awake Inquiry into the Human Nature of Time. Aurum, London.

Cassone, V.M. and Menaker, M. 1984. Is the avian circadian system a neuroendocrine loop? J.Exper.Zool. 232:536-549.

Cloudsley-Thompson, J. 1980. Biological Clocks, Their Functions in Nature. Weidenfeld & Nicolson, London.

Coveney, P. and R.Highfield, 1990. The Arrow of Time: A Voyage Through Science to Solve Time's Greatest Mystery. Fawcett Columbine, New York.

Daan, S. and Aschoff, J. 1975. Circadian rhythms of locomotor activity in captive birds and mammals: their variation with season and latitude. Oecologia: 18:269-316.

Daan, S. and Koene, P. 1981. On the timing of foraging flights by oystercatchers, Haematopus ostralegus, on tidal mudflats. Netherl.J.Sea Res. 15:1-22.

Daan, S., 1995. Circadian tuning of motivation. A little organ of yesterday? Acta neuropsychiatrica 7:21-23.

Darwin, C. 1858. On the tendency of species to form varieties; and on the perpetuation of varieties and species by natural means of selection. J. of the Linnean Soc. 3:45-62.

Darwin, C. 1859. On the origin of species by means of natural selection, or preservation of

favoured reaces in the struggle for life. Murray, London.

Darwin, C. 1868. The variation of animals and plants under domestication. Murray, London.

Darwin, C. 1871. The descent of man, and selection in relation to sex. Murray, London.

Darwin, C. 1872. The expression of the emotions in man and animals. Murray, London.

Darwin, C. 1880. The power of movement in plants (assisted by F. Darwin). Murray, London.

Darwin, C. 1881. The formation of vegetable mould, through the action of worms, with observations on their habits. Murray, London.

David-Gray, Z.K., Janssen, J.W.H., DeGrip, W.J., Nevo E. and Foster, R.G., 1998. Light detection in a 'blind' mammal. Nature Neurosci. 1:655-656.

Davis-Walton, J. and Sherman, P.W., 1994. Sleep Arrhythmia in the Eusocial Naked Mole-Rat. Naturwissenschaften 81:272-275.

Dawkins R (1976) The selfish gene. Oxford University Press.

Dawkins R (1982) The extended phenotype. Freeman.

Dawkins R (1986) The blind watchmaker. Longman.

Dawkins R (1995) River out of Eden. Weidenfeld & Nicolson.

De Candolle, A.P. 1832. Physiologie Vegetale. Paris: Bechet jeune.

De Mairan, J.J.O. 1729. Observation Botanique, Histoire de l'Academie Royale des Sciences, Paris, p.35.

DeCoursey, P. J. 1960. Phase Control of Activity in a Rodent, Cold Spring Harbor Symposia on Quantitative Biology, Vol.25, p.49.

DeCoursey, P.J. 1990. Circadian photoentrainment in nocturnal mammals: ecological overtones. Biol.Behav. 15:213-238.

DeCoursey, P.J., Krulas, J.R., Mele, G and Holley, D.C. 1997. Circadian performance of suprachiasmatic nuclei (SCN)-lesioned antelope ground squirrels in a desert enclosure. Physiol.Behav. 62:1099-1108.

DeCoursey, P.J., Walker, J.K. and Smith, S.A. 2000. A circadian pacemaker in free-living chipmunks: essential for survival? J.Comp.Physiol.A 186:169-180.

Dennett, D.C. 1995. Darwin's dangerous idea: Evolution and the meanings of life. Allen Lane.

Dewsbury, D.A., 1992. On the problems studied in ethology, comparative psychology, and animal behavior. Ethology 92:89-107.

Diamond, J. 1986. "Laboratory Experiments, Field Experiments, and Natural Experiments", IN:

J Diamond and TJ Case (eds.), Community Ecology. New York: Harper & Row, 3-22.

Duhamel de Monceau, H.L. 1758. La Physique des Arbres. Paris: H.L.Guerin & L.F.Delatour.

Dunlap, J.C., 1999. Molecular Bases for Circadian Clocks. Cell 96:271-290.

Edmunds, L.N., 1988. Cellular and Molecular Bases of Biological Clocks: Models and Mechanisms for Circadian Timekeeping. Springer-Verlag.

Enright, J.T., 1970. Ecological aspects of endogenous rhythmicity. Annu.Rev.Ecol.System. 1:221-238.

Enright, T.J., 1975. The Circadian Tape Recorder and its Entrainment. In: F.J.Vernberg, ed., Physiological Adaptation to the Environment. pp.465-476. Intext Educational Publishers.

Francis D, Diorio J, Liu D, Meaney MJ., (1999) Nongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat, Science 286:1155-1158.

Frazer, J.T., 1996. Time and the Origin of Life. In: J.T.Fraser and M.P.Soulsby, eds., Dimensions of Time and Life. International Universities Press.

Gannett, L. 1999. What's in a cause?: the pragmatic dimensions of genetic explanations. Biology and Philosophy 14: 349-374.

Garner, W.W. and H.A. Allard, 1920a. Effect of the Relative Length of Day and Night and Other Factors of the Environment on Growth and Reproduction in Plants. J. of Agricultural Research, Vol.18.,pp.553-606

Garner, W.W. and H.A. Allard. 1920. Flowering and Fruiting of Plants as Controlled by the Length of the Day. Yearbook of the Department of Agriculture, 1920. Washington: U.S. Government Printing Office., pp.377-400.

Godfrey-Smith, P. 1999. Genes ands Codes: Lessons from the Philosophy of Mind? In: Hardcastle VG, ed. Where Biology Meets Psychology. pp.305-331. The MIT Press.

Goldman, B.D., 1999. Circadian rhythms in subterranean mammals. (talk abstract) International Conference on Chronobiology, Washington, D.C.

Goodwin, B. 1963. Temporal Organization in Cells. Academic Press, London & New York.

Goodwin, B.C., 1966. An entrainment model for timed enzyme synthesis in bacteria. Nature 209:477-481.

Griffiths, P. and Gray, R. 1994. Developmental systems and evolutionary explanation. Journal of Philosophy 91:227-304.

Guyomarc'h, C., Lumineau, S. and Richard, J.P., 1998. Circadian rhythm of activity in Japanese quail in constant darkness: Variability of clarity and possibility of selection. Chronobiology Int 15:219-230.

Gvakharia, B.O., Kilgore, J.A., Bebas, P. and Giebultowitz, J.M. 2000. Temporal and spatial expression of the period gene in the reproductive system of the coddling moth. J.Biol.Rhythms 15:4-12.

Hahn, T.P, Boswell, T., Wingfield, J.C. and Ball, G.F. 1997. Temporal flexibility in avian reproduction: patterns and mechanisms. Current Ornith. 14:39-80.

Halberg, F. 1964. A Spectrum of Low-Frequency Rhythms in Physiological Function, lecture, U.C.Berkeley, Nov.3.1964.

Hall, J.C. 1996. Are cycling gene products as internal Zeitgebers no longer the Zeitgeist of chronobiology? Neuron 17:799-802.

Harker, J.T. 1960. Endocrine and Nervous Factors in Insect Circadian Rhythms. In Cold Spring Harbor Symposia on Quantitative Biology, Vol.25.,pp.279-87.

Heideman, P.D. and Bronson, F.H. 1991. Characteristics of agenetic polymorphism for reproductive photoresponsiveness in the white-footed mouse (Peromyscus leucopus). Biol.Reprod. 44:1189-1196.

Heideman, P.D. and Bronson, F.H. 1994. An endogenous circannual rhythm of reproduction in a tropical bat, Anoura geoffroyi, is not entrained by photoperiod. Biol. Reprod. 50:607-614.

Heideman, P.D., Bhatnagar, K.P., Hilton, F.K. and Bronson, F.H. 1996. Melatonin rhythms and pineal structure in a tropical bat, Anoura geoffroyi, that does not use photoperiod to regulate seasonal reproduction. J.Pineal Res. 20:90-97.

Heideman, P.D., Bruno, T.A., Singley, J.W. and Smedley, J.V. 2000. Genetic variation in photoperiodism in Peromyscuc leucopus: geographic variation in an alternative life-history strategy. Mammalogy

Helfrich-Forster, C. 2000. Differential control of morning and evening components in the activity rhythm of Drosophila melanogaster - sex-specific differences suggest a different quality of activity. J.Biol.Rhythms 15:135-154.

Heinlein, R.A., 1973. Time Enough For Love.

Hermann B. and A.Danielmeyer, 1994, Bone Structures Reflecting Rhythm, Seasonality, and Life-Style of Past Human Populations, Naturwissenschaften 81: 399-401.

Hubbard and Wald Exploding the gene myth

Hurd, M.W. and Ralph, M.R. 1998. The significance of circadian organization for longevity in the golden hamster. J.Biol.Rhythms 13:430-436.

Jeon, M., Gardner, H.F., Miller, E.A., Deshler, J. and Rougvie, A.E., 1999. Similarity of the C.elegans Developmental Timing Protein LIN-42 to Circadian Rhythm Proteins. Science 286: 1141-1146.

Johnson, C.H. and Goden, S.S. 1999. Circadian programs in cyanobacteria: adaptiveness and mechanism. Annu.Rev.Microbiol. 53:389-409.

Kaneko, M., Hamblen, M.J. and Hall, J.C. 2000 Involvement of th eperiod gene in developmental time-memory: effect of the per-short mutation on phase shifts induced by light pulses delivered to Drosophila larvae. J.Biol.Rhythms 15:13-30.

Kauffman, S. A. 1993. The Origins of Order: Self-Organization and the Selection in Evolution. Oxford University Press.

Kauffman, S. A. 1995. At Home in the Universe: The Search for the Laws of Self-Organization and Complexity. Oxford University Press.

Keeley, B.L., 1999. Fixing content and function in neurobiological systems: the neuroethology of electroreception. Biology and Philosophy 14:395-430.

Keller, E.F. 1995. Refiguring Life: Metaphors of Twentieth-Century Biology. Columbia University Press, New York.

Kitcher, P. 1999. The Hegemony of Molecular Biology. Biology and Philosophy 14: 195-210.

Krishnan, B., Dryer, S.E. and Hardin, P.E. 1999. Circadian rhythms in olfactory responses of Drosophila melanogaster. Nature 400:375-378.

Kyriacou, C.P. and Hall, J.C. 1980. Circadian rhythm mutations in Drosophila melanogaster affect short-term fluctuations in the male's courtship song. Proc.Natl.Acad.Sci.USA 77:6729-6733.

Kyriacou, C.P., Greenacre, M.L., Thackeray, J.R. and Hall, J.C. 1993. Genetic and molecular analysis of song rhythms in Drosophila. In: Molecular genetics of biological rhythms, Young, M.W., ed. Marcel Dekker, New York.

Kyriacou, C.P., Oldroyd, M., Wood, J., Sharp, M. and Hill, M. 1990. Clock mutations alter developmental timing in Drosophila. Heredity 64:395-401.

Lakin-Thomas, P.L. 2000. Circadian rhythms: new functions for old clock genes? Trends Gen. 16:135-142.

Lakin-Thomas, P.L. and Johnson C.H. 1999. Commentary: molecular and cellular models of circadian systems. J.Biol.Rhythms 14: 486-489.

Lewontin, R.1992. The Dream of the Human Genome. New York Review of Books, May 28:31-40.

Linnaeus, C. 1751. Philosophia Botanica, Stockholm.

Lintilhac PM (1999) Toward a theory of cellularity - Speculations on the nature of the living cell. BioScience 49:59-68.

Luce, G.G. 1971. Biological Rhythms in Human & Animal Physiology. Dover, NY.

Marques, M.D. and Hoenen, S.N.M., 1999. Altered circadian patterns in a cave insect: signs of temporal adaptation? (poster abstract) International Conference on Chronobiology, Washington, D.C.

Maynard-Smith, J. and Szathmary, E. 1999. The Origins of Life : From the Birth of Life to the Origin of Language. Oxford University Press.

Moore, D., Angel, J.E., Cheeseman, I.M., Fahrbach, S.E. and Robinson, G.E. 1998. Timekeeping in the honey bee colony: integration of circadian rhtyhms and division of labor. Behav.Ecol. Sociobiol. 43:147-160.

Moore-Ede, M.C., F.M.Sulzman and C.A.Fuller. 1982. The Clocks That Time Us. Harvard University Press.

Mrosovsky N (1990) Rheostasis: The Physiology of Change. Oxford University Press.

Nagai, K. and Oishi, T., 1999. Behavioral rhythms of Japanese Newts, Cynopus pyrrhogaster, under experimental conditions: analysis of Zeitgebers. (poster abstract) International Conference on Chronobiology, Washington, D.C.

Nelin and Lindee 1995 The DNA Mystique

Newport, G. 1837. On the Temperature of Insects and its Connection with the Function of Respiration and Circulation in the Class of Invertebrate Animals. Philosophical Transactions, Table VII,p.307.

Nijhout, H.F. 1990. Metaphors and the Role of Genes in Development. BioEssays 12:441-446.

Nijhout, H.F. 1994. Insect Hormones. Princeton University Press, NJ.

Nijhout, H.F. 1999. Control mechanisms of polyphenic development in insects. BioSci. 49:181-192.

Orr, R.T. 1970. Animals In Migration. The MacMillan Co.

Ouyang, Y., Andersson, C.R., Kondo, T., Golden, S.S. and Johnson, C.H., 1998. Resonating circadian clocks enhance fitness in cyanobacteria. Proc.Natl.Acad.Sci.USA 95:8660-8664.

Oyama, S. 1985. The ontogeny of information: Developmental systems and evolution. Cambridge University Press.

Paterson, H.E.H, 1993. Evolution and the Recognition Concept of Species: Collected Writings. S.F.McEvey, ed., The John Hopkins University Press.

Pavlidis, T., 1971. Populations of biochemical oscillators as circadian clocks. J.Theor.Biol. 33:319-338.

Pennisi, E., 1997. New developmental clock discovered. Science 278:1564.

Pfeffer, W.F.P. 1880, 1897, 1899, (reprinted1903.,1905.), Pfeffer's Physiology of Plants, Volumes I -III, Ed. and Trans. Alfred J.Ewert., Oxford .

Pittendrigh, C.S. 1960. Circadian rhythms and circadian organization in living systems. Cold Spring Harbor Symposia on Quantitative Biology 25:159-182.

Pittendrigh, C.S. 1961. On temporal organization in living systems. Harvey Lectures 56:93-125.

Pittendrigh, C.S. and Bruce, V.G., 1959. Daily rhythms as coupled oscillator systems: and their relation to thermo- and photo-periodism. In: R.B.Withrow, ed., Photoperiodism and Related Phenomena in Plants and Animals. pp.475-505. AAAS #55, Washington D.C.

Pittendrigh, C.S. and Minis, D.H. 1972. Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster. Proc.Natl.Acad.Sci.USA 69:1537-1539.

Pittendrigh, C.S., 1958. Adaptation, natural selection, and behavior., In: A Roe, GG Simpson, eds., Behavior and Evolution, Chapter 18 (pp. 390-416), Yale University Press.

Pittendrigh, C.S., 1965. Biological clocks: the functions, ancient and modern, of circadian oscillations. In: Science in the Sixties, Proceedings of the 1965 Cloudcroft Symposium. Air Force Office of Scientific Research, pp. 96-111.

Pittendrigh, C.S., 1967. Circadian rhythms, space research, and manned space flight. In: Life Sciences and Space Research 5:122-134. North-Holland, Amsterdam.

Pittendrigh, C.S., 1981. Circadian systems: general perspective. In: Handbook of behavioral neurobiology, Vol. 5, Plenum Press, New York, pp:57-80.

Pittendrigh, C.S., 1993. Temporal Organization: Reflections of a Darwininan Clock-Watcher. Annu.Rev.Physiol. 1993. 55:17-54.

Renn, S.C.P., Rark, J.H., Rosbash, M., Hall, J.C. and Taghert, P.H. 1999. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99:791-802.

Roenneberg, T. and Merrow, M. 1998. Molecular circadian oscillators: an alternative hypothesis. J.Biol.Rhythms 13:167179.

Roenneberg, T. and Merrow, M. 1999. Circadian systems and metabolism. J.Biol.Rhythms 14: 449-459.

Rose, S. 1998. Lifelines: Biology Beyond Determinism. Oxford University Press, Oxford, UK.

Roth J.J. and E.C. Roth, 1980, The Parietal-Pineal Complex Among Paleovertebrates: Evidence for Temperature Regulation In A Cold Look at the Warm-Blooded Dinosaurs (R.D.K.Thomas and E.C.Olson, Eds.) AAAS Selected Symposium 28, Westview Press, Boulder, CO. pp.189-231.

Sauer 1958. Celestial Navigation by Birds. Sci.Am. 199:42-47.

Sauer, E.G.F. and E.M.Sauer, 1960. Star Navigation of Nocturnal Migrating Birds. In Cold Spring Harbor Symposia on Quantitative Biology, Vol. 25. pp.463-473.

Sauer, E.G.F., 1957. Die Sternenorientierung nachtlich ziehander Grasmucken. Zeitsch rift fur Tierpsychologie, Vol 14. pp.29-70.

Sauman, I. and Reppert, S.M. 1996. Circadian clock neurons in the silkmoth Antheraea pernyi: novel mechanisms of period protein regulation. Neuron: 17:889-900.

Saunders, D.S. 1972. Circadian Control of Larval Growth Rate in Sarcophaga argyrostoma. Proc.Natl.Acad.Sci.USA 69:2738-2740.

Sawara, Y., Azuma, N., Hino, K., Fukui, K., Demachi, G. and Sakuyama, M. 1990. Feeding activity of the grey heron Ardea cinerea in tidal and non-tidal environments. Jap.J.Ornith. 39:45-52.

Sawyer, L.A., Hennesy, J.M., Peixoto, A.A., Rosato, E., Parkinson, H., Costa, R. and Kyriacou, C.P., 1997. Natural Variation in a Drosophila Clock Gene and Temperature Compensation.

Schlinger, B.A. 1998. Sexual differentiation of avian brain and behavior: current views on

gonadal hormone-dependent and independent mechanisms. Annu.Rew.Physiol. 60:407-429.

Schroedinger, E.1944. What is Life? Cambridge University Press, Cambridge, UK.

Schwabl, H. Yolk is a source of maternal testosterone for developing birds. Proc.Natl.Acad.Sci.USA 90:11446-11450.

Sheeba, V., Sharma, V.K., Chandrashekaran, M.K. and Joshi, A., 1999. Persistence of Eclosion Rhythm in Drosophila melanogaster After 600 Generations in an Aperiodic Environment. Naturwissenschaften 86: 448-449.

Shettleworth, S.J., 1998. Cognition, Evolution, and Behavior. Oxford University Press.

Skutelsky, O. 1996. Predation risk and state-dependent foraging in scorpions: effects of moonlight on foraging in the scorpion Buthus occitanus. Anim. Behav. 52:49-57.

Sterelny, K. and Griffiths, P.E. 1999. Sex and Death: An Introduction to Philosophy of Biology. The University of Chicago Press, Chicago and London.

Sweeney, B.M. 1960. The Photosynthetic Rhythm in Single Cells of Gonyaulax Polyedra. Cold Spring Harbor Symposia on Quantitative Biology, Vol.25., p.145.

Tinbergen, N., 1963. On aims and methods of ethology. Zeitschrift fur Tierspsychologie 20:410-433.

Trajano, E. and Menna-Barreto, L., 1999. Locomotor activity rhythms in cave catfishes, genus Taunayia, from eastern Brazil (Teleostei: Siluriformes: Heptapterinae). (poster abstract) International Conference on Chronobiology, Washington, D.C.

Trut, L.N. 1999. Early canid domestication: the farm-fox experiment. Amer. Sci. 87:160-169.

Turek, F.W. 2000. What is sleep? What is it good for? J.Biol.Rhythms 15:83-85.

Underwood, H., Siopes, T. and Edmonds, K. 1997b. Eye and gonad: role in the dual-oscillator circadian system of female Japanese quail. Am.J.Physiol.272:R172-R182.

Underwood, H., Steele, C.T. and Zivkovic, B.D. 2000. Circadian organization and the role of the pineal in birds. Microscopy Research and Techniques.

Underwood, H., Wassmer, G.T. and Page, T. 1997a. Daily and seasonal rhythms. In: Handbook of physiology, sect.13, comparative physiology, V.II, Dantzler, W.H., ed, pp.1653-1763, Oxford University Press, New York.

Vafopolou, X. and Steel, C.G.H. 1991. Circadian regulation of synthesis of ecdysteroids by prothoracic glands of the insect Rhodnius prolixus: evidence of a dual oscillator system. Gen.Comp.Endocrin. 83:27-34.

Vafopolou, X. and Steel, C.G.H. 1998. A photosensitive circadian oscillator in an insect endocrine gland: photic induction of rhtyhmic steroidogenesis in vitro. J.Comp.Physiol A 182:343-349.

Van Valen, L. 1973. Festschrift. Science 180: 488.

Waddington, C.H., 1942. Canalization of development and the inheritance of acquired characters. Nature 150:563-565.

Ward, R.R. 1971. The Living Clocks. Alfred A. Knopf, New York.

Warman, G.R. and Lewis, R.D. 1997. Description of the photoperiodic control of larval burrowing in the blowly Lucilia cuprina: a novel index for photoperiodic research. Chronobiol. Internat. 14:247-252.

Wikelski, M. and Hau, M. 1995. Is there an endogenous tidal foraging rhythm in marine iguanas? J.Biol.Rhythms 10:335-350.

Williams, G.C., 1966. Adaptation and Natural Selection. Princeton University Press.

Williams, K.S. and Simon C. 1995. The ecology, behavior, and evolution of periodical cicadas. Annu.Rev.Entomol. 40:269-295.

Wiltschko R. and W.Wiltschko, 1995, Magnetic Orientation in Animals, Springer-Verlag, Berlin.

Wimsatt, W.C., 1986. Developmental Constraints, Generative Entrenchment, and the Innate-Acquired Distinction. In: W.Bechtel, ed., Integrating Scientific Disciplines, pp.185-208. Martinus-Nijhoff.

Wimsatt, W.C., 1999. Generativity, Entrenchment, Evolution, and Innateness: Philosophy, Evolutionary Biology, and Conceptual Foundations of Science. In: V.G.Hardcastle, ed., Where Biology Meets Psychology, pp.139-179. The MIT Press.

Winfree, A.T., 1990. The Geometry of Biological Time. Springer-Verlag.

Wingfield, J.C., Hahn, T.P. and Doak, D. 1993. Integration of environmental factors regulating transitions of physiological state, morphology and behaviour. In: Avian Endocrinology. Sharp, P.J., ed. J.of Endocr., Bristol., pp.111-122.

Wingfield, J.C., Maney, D.L., Breuner, C>W., Jacobs, J.D., Lynn, S., Ramenofsky, M. and Richardson, R.D. 1998. Ecological bases of hormone-behavior interactions: the "Emergency Life History Stage". Amer.Zool. 38:191-206.

Zivkovic, B.D., Underwood, H., Steele, C.T. and Edmonds, K., 1999. Formal properties of the circadian and photoperiodic systems of Japanese quail: Phase-response curve and effects of T-cycles. J.Biol.Rhythms 14:378-390.