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Time in living systems
Alexei A. Sharov Genetics Laboratory, Nat ional Inst itute on Aging, NIA/NIH, Balt imore, USA 1. Time and change There is no consensus amo ng scientists on what t ime is. Most physicists view time and space as fundamental properties of the world, where change is described as a trajecto ry in space and t ime. They optimist ically assume that all changes can be explained in terms of effect ive cause. However, Aristotle po inted out that effect ive cause is only one of four possible kinds of causat ion, and not every change can be fully explained by fo llowing trajectories in t ime and space. According to Aristotle, change is a more fundamental category than t ime; in fact, time is made of changes. Also time is not universal, it can be specific for some systems. This view of time is assumed by several bio logists who think that living systems have their own time scales and time sequences. For example, organisms show different pace in their development or aging. In order to study time we first need to learn how to study change. This quest ion was invest igated in detail by a Russian paleobot anist, Sergei Meyen. His main ideas can be summarized as follows: 1. Change is first qualitat ive and only then quant itative; time represents qualit y (archet ype). Thus, Meyen called his conception of t ime as "t ypological time". 2. To detect change we need a model of a system (i.e., a list of parts and relations between parts). 3. Change fo llows certain rules (logic) and we need to reconstruct these rules 4. Change leaves footprints which can be used for temporal reconstructions Let us first address the problem o f modeling. A living organism can be modeled as a system of interconnected parts. For example, fish has head, eyes, fins, tail. More parts can be found inside. There is liver, guts, gills, heart, and other organs.

Meyen suggested a term "merono my" for a science about parts of systems and principles of partitioning. Paleonto logists often find iso lated parts of organisms (e.g., leaves or fruits of plants), which are difficult t o classify unless so mebody is lucky to find an attachment o f a part to the who le organism. Each part can be further partit ioned into smaller parts up to the cellular or even


mo lecular level, and each level o f organizat ion brings addit io nal details about the structure and function of each part. Change of organisms in the individual life or in evolut ion can be described in terms of alterat ion of the composit ion of parts or relations between parts. For example, a tadpole has a tail, but the fro g which develops fro m it has no t ail. The evolutio n of fish can be described by the change of part size (e.g., paddlefish has a long nose), or by the loss of parts (e.g., eels lost most of the fins that other fish have). Using a model o f an animal we can start understanding the rules (i.e., logic) of animal evo lut ion. We can learn which new parts can emerge, and how relations can be modified. Below is an example fro m the famous book of D'Arcy Tho mpson "On Growth and For m". The picture shows that the change of metric (i.e., distance between parts) can transform one kind of fish into anot her, or transform the skull o f a monkey into the skull o f a human. These transfor mations take time, so we can measure evo lutionary time by the degree of geometric change.

Dr. Meyen was specifically interested in fo llowing the logic of leaf evo lut ion. It appears that the evo lut ion of leaves follows its own internal logic, sho wn below. A leaf can be modified in 3 basic ways: (a) splitt ing the end into two branches, (b) producing feather-like nodes, or (c) palmlike nodes. Also, there may be combinat ions of different patterns, as shown in the picture which is taken fro m the book "Fundamentals of Paleonto logy" by Sergei Meyen.


2. Life cycle, individual time Now let us switch from evo lut ionary t ime to a shorter time scale, which is individual t ime or a life cycle. Change beco mes time o nly when it is reproducible. The main reproducible element of any living organism if it s life cycle. The butterfly lays the eggs, small caterpillars emerge from eggs, they start feeding and growing, and then a caterpillar beco mes a mot ionless pupae, attached to a branch. Finally, a new butterfly emerges fro m the pupae.


Platonic philo sophers view change as a destruction of for m, which may be true in the case of death. However, the change can also make a new level of for m as in the life cycle. We tend to consider an organism in it s current form, which is a wrong approach because the organism is a circular process of its life cycle. Some parts of the organism may be not functional current ly, but they are needed for the next phase of the cycle. You cannot understand a caterpillar unless you know that it will eventually beco me a butterfly. We, humans, also have a reproducible life cycle, which is a form of our existence. We can understand our life at a new level if we think that any stage of our physical and psycho logical development is transient is a part of a life cycle. Several organs change their function as a human grows up and then ages. Many philo sophers and artists attempted to comprehend human life fro m the perspective of the life cycle, and here examples o f paint ings on this topic.

Three ages of women (fragment) Gustav Klimt

Old and young Huang Shan Shou

Aging should be viewed as a part of our nature, as our bio logical time scale. Also, aging is not just a fate, it can be modified if we learn its logic. Below is the logo of the National Insitute on Aging (where I work) showing that the aging clock can be adjusted, and we can throw an extra handful o f sand into our sand clock.


The life cycle has internal logic, which is extremely complex and we understand only a small fraction o f it. Here is an example of a logical switch in the early development of Drosophila embryo. Two major genes control the format ion of the anterior-posterior polarit y o f the embryo: hunchback is transcribed in the entire egg, but nanos is transcribed only in the posterior pole. Nanos protein binds to hunchback mRNA and blocks its translat ion. Thus, at the protein level, the embryo has two opposite gradients of bot h genes, which affect the activation and suppression of other genes that control the for mation of body parts along the anterior-posterior axis.

Messenger RNA
anterior

Protein level
posterior

Egg

Drosophila fly

Nanos blocks translation of hunchback

At a later stage, body segmentation is formed and maintained via segment-specific expressio n of several ho meobox genes shown by different colors below:

3. Tempofixation Past change leave their footprints which allo w us to reconstruct histo rical events. Sergei Meyen was a paleontologist; thus it was his direct professional interest to make histo rical reco nstruction of such footprints of time which he called "tempo fixat ors". The most commo n tempofixat ion is tree rings which indicate the rat e of growth, climate changes, pest insect outbreaks, and forest fires. Smaller chambers o f the shell o f the Nautilus mo llusk represent its size at earlier stages of development.


Tree rings

Shell of Nautilus

Tempofixat ion is not designed for scientists who do historical reconstruct ions, it is useful for the organisms themselves. For example, tree rings have important structural and water-conducting functions. Neurons layers in the cortex of the brain (see below) represent mult iple waves of neuron migrat ion, and t his layered structure is very important for brain funct ionalit y.

Paleontologists used fossilized organisms for reconstruction of past evo lution. This is the ancient bird Archaeopteryx, trilobites (giant sea cockroaches), giant dragonflies which has not hing in commo n with contemporary dragonflies.
Archeopterix Trilobites Paleodictyoptera


Paleontologists are interested not in just individual organisms but also at reconstruction of ecosystems of the past. It is important to know which organisms lived together at specific t ime and place. Fossils can be dated by evolut ionary periods. For example, the Ordovician period was the era of gigant ic cephalopods and trilo bites, and the Jurassic period was the era of dinosaurs. Evolut ionary periods is a perfect example of a qualitat ive time scale. Each period has its own key features, and the abso lute time is not that import ant.

4. Living systems make their own time So far we were using the Aristotle's concept ion of time as change in living systems. But what is the source of change?Here I want to focus on the idea that change is controlled/encoded by living systems, in ot her words, living systems make their o wn time. Living organisms are selfreferential systems. Thus, external observer is not needed to detect or make change. Estonian bio logist Jacob von Uexkull developed a theory of meaning (Bedeutungslehre, 1940).

Jakob von UexkЭll (1864-1944)


He suggested that all organisms develop a model of their environment, which he called Umwelt. Organisms make meanings out of objects, interpreting them as food, shelters, or enemies. Living systems are different from non-living objects because they can create new meanings. Organisms perceive the world through their funct ions and their tools. According to the law of instrument attributed to Mark Twain, "To a man with a hammer, everything looks like a nail". By making a new tool or organ, organisms can modify their perception of the world. This concept has developed into a novel area of science called Biosemiot ics (see http://www.biosemiot ics.org). The main thesis o f bio semiot ics is that Life and Meaning are coextensive. Every living organism makes and co mmunicates a model of its environment, and all meanings are produced in this way. This idea is oppo site to the Platonic philosophy, which considers all forms and meanings as given a-priori. Time can be viewed as a part of the Umwelt of an organism, which is needed to organize individual processes into funct ional behavior. Some processes need to be synchronized, whereas others should be invoked sequentially in a specific order. Even single-cell organisms can make their Umwelt and their time; thus, the brain is not necessary for making models. Nucleus is the brain o f eukar yotic cell. It carries lo ng-t erm memo ry which is communicated across generat ions and is represented by the geno me. In addit ion it carries short-term memor y represented by epigenet ic marks, which are various modifications of DNA-binding proteins called histones. Histones can be methylated, acetylated, phosphorylated, or ubiquet inated, and these modifications control the activit y of genes in the geno me. There is a hypothesis that brain memory is based on the epigenet ic memory o f individual neurons. Let us consider the most fundamental temporal pheno menon in bio logy which self-reproduction. Because the majorit y of living organisms are represented by cells, self-reproduction is implemented as a cell cycle. For example, bacterial cells grow and then divide to produce offspring cells. The divis io n of a bacterial cell starts with the duplicat ion of its circular DNA. DNA rings are distr ibuted between daughter cells, and they beco me separated by a cell wall. This process is repeated indefinitely unt il resources are available in the environment. Most organisms are much bigger and more complex than bacteria. They are called eukaryot ic organisms. Their cells have a nucleus, and DNA is organized into mult iple chromoso mes as shown below. The reproduction cycle of the eukaryot ic cell is much more complex, it can be viewed as a dance of chro mosomes with macromo lecular part ners like microtubules, centrosomes, and others. Chro mosomes duplicate, condense, and make pairs along the center of the cell. Nuclear envelope disintegrates into small vesicles. Then chromoso mes are pulled to the poles and de-condense t here.


The quest ion is how this dance of chromoso mes is designed and orchestrated. Cell divisio n is a living clock with periodic divis io ns. A clock has a barrel wit h a spring, and various wheels. In the cell there are no wheels, however t here is a perfect ly tuned wet mechanism which controls the cycle. I brief, each chromoso me in a cell is a huge DNA mo lecule which is a sequence of nucleotides. All chro mosomes in a human geno me carry about 3 billio n nucleotides which we can read as A, T, G, and C charact ers. Some part s of this sequence are used to encode proteins, they are called genes. Genes are first transcribed, which means making an RNA copy of the gene. Then the protein is manufactured using RNA sequence as a template. Some proteins can regulate the activit y o f other genes; they are called transcription factors. These transcript ion factors can bind to a specific short sequence of nucleotides near the beginning of the gene, and then they can either act ivate or suppress the transcription of the gene. Regulation of gene activit y is a very complex process, which invo lves hundreds o f regulatory proteins wit h sophist icated rules of assembly and disassembly. They make logical switches resembling human logic. Some regulators can start working only in the presence of specific partners, but they beco me inactivated by specific repressors. Bio logists still understand only a small portion of these interactions. To add the complexit y, there is so called "histo ne code" which is the basis for


epigenetic short-term memor y in the nucleus. It is also controlled by hundreds of proteins with logical switches.
Promoter

Gene

Introns

Exons

DNA
3,000,000,000 nucleotides

mRNA

DNA
RNA polymerase
Transcript ion factor

Protein synthesis

DNA

mRNA

Histones regulate gene functions

Mechanisms o f cell cycle were studied in more details in the yeast. There is a techno logy called "microarray" which makes it possible to measure the act ivit y o f all genes in the geno me at each time point. The left panel o f the figure below shows the results of analysis o f mult iple microarrays taken at different time points through the cell cycle (cells are synchronized). Data are shown as a matrix where genes are rows, time points are columns, and gene expressio n is color-coded. It appears that a large number o f genes have a cyclic act ivit y synchro nized wit h the cell cycle. Analys is of regulatory genes in this data set has led to a model of yeast cell cycle, shown at the right panel o f the figure below. This is a simplified versio n of the model which, however, covers the most important regulatory switches.


Data Wiring diagram

Time

Circadian clock is another cyclic process in organisms. In contrast to the cell cyc le of yeast, this clock is adjustable by external light periodicit y. As a result, the organism can ant icipate environmental changes by addressing its circadian clock. Molecular mechanisms of this clock include several key proteins like transcript ion factors Per2, Cry1, and others. Circadian clock includes cell cycle-related genes and it is often synchronized with cell divis io n.
Circadian clock Part of the mechanism


Photoperiodism adds more complexit y on the top of the circadian clock. Organisms can detect changes in the length of light and dark periods of the day and adjust their activit y to the seasonal changes. Here is an example o f the well-known Christ mas plant Poinsettia. If grown in lo ng day condit ions, poinsettia produces only green leaves and no flowers. However, after transit ion to a short day and lo ng night, it produces red-color leaves which we like to see on Christmas. The actual flowers are very small and are hardly seen on this picture. Thus, plants and animals developed their own calendar based on photoperiodism.
Poinsettia Mechanism

FT = flowering locus T

Molecular funct ions of organisms are often described as "mechanisms". Unfort unately, t he word "mechanism" has unjust ified connotation of so mething foreign to life, so mething that often destroys life. However, some art ists like Dali and Ast rin realized that mechanisms are alive in some sense.

A. Astrin S. Dali

The obvious difference is that mechanisms are human products; thus, they are not autonomous, whereas organisms are auto nomous and autopoietic, which means self-pro ducing. Famous bio logists Maturana and Varella developed a theory o f autopoiesis and applied it to the funct ion


of the brain. Mechanis ms can be viewed as components of the human autopoietic system. They are external and replaceable organs, which support human production system that includes agriculture, industry, and science. Cellular structures and mo lecules are also manufactured (not by humans but by the cell), so they also can be called mechanisms and art ifacts. These mechanisms include various kinds of clocks which determine the struct ure of internal t ime. In other words, we build our own time. In conclusio n I would like to point out the unit y o f time and life. This unit y was foreseen by Heidegger who called his famous book "Being and time". Life cannot exist without making clocks because: (1) life is based on self-reproduction, and (2) self-reproduction is a periodic clock-like process. Does time exist without life? We can reconstruct past events, including the origin o f life; but we (who do the reconstruction) are alive. Time structure is needed for preservation and communicat ion of useful functions (e.g., well tuned sequence of processes in cell divisio n, life cycle) ; and useful funct ions and communicat ion exist only in living o rganisms. Thus, time is a product of life. However, we can extrapolate processes beyo nd human life and bio logical evolut ion. But we should not forget that time without life is an abstraction. 5. Conclusions 1. 2. 3. 4. Time represents reproducible change (Aristotle's time) Reproducible change requires modeling and logic Time is a product of life and it is organism-specific Various cyclic processes in organisms emerged in the course of evo lut ion: cell cycle, circadian clock, photoperiodism 5. Living organisms are autonomous and autopoiet ic clocks; the boundary between organisms and mechanisms is blurred 6. Time and life are inseparable; time wit hout life is an abstraction