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1034 Animals Made of Stem Cells: Immortality and Regeneration vs. Brains, Blood, and the Cambrian Explosion Chris Phoenix [email protected] Why can the descendants of ancient Precambrian animals regenerate and repair themselves better than modern animals, and reproduce more flexibly? And why did modern animal forms arise in just a few million years at the start of the Cambrian period? Modern animals may have made a successful tradeoff, drastically reducing the flexibility of their cells in exchange for more complicated tissues and more reliable networks. This tradeoff may have enabled elaborate nutrient distribution networks, intricate organs, and brains capable of learning and self-organization. These innovations would have created vast new opportunities for new body types and functions - but at the cost of regeneration. At a molecular level, the “enabling technology” may have been the harnessing of epigenetics during embryogenesis to transform stem cells into differentiated somatic cells. 1 Introduction Animals originating in the Cambrian, which I will call “modern,” have notably more advanced organs than Precambrian animals, and more complex body types and functional repertoires. At the same time, animals of Precambrian origin have notably greater powers of regeneration. 1035 A single, wildly successful innovation could have enabled increased tissue intricacy, network reliability, and brain function, and this same innovation would necessarily have resulted in reduced cellular flexibility and thus reduced regenerative capacity. This innovation was cellular differentiation: the creation of somatic cells with little or no flexibility. Somatic cells are created from stem cells by inducing near-permanent changes in gene expression. Formerly-random epigenetic mechanisms could have been adapted to make such changes in response to intense but transient chemical signals. In effect, this implies that Precambrian animals were built entirely of stem cells induced to temporary cooperation through ongoing chemical signaling subject to a tradeoff between metabolic cost and precision. The regenerative and reproductive advantages of fully flexible cells are considerable, and may have made differentiation unlikely to evolve in any given millennium even after conditions were ripe for it even though the development of differentiation might only have required a modest modification of epigenetic mechanisms already in place. Once differentiation developed and began to persist, organisms with reliable intercalated tissues, network structures, and synaptic learning could quickly evolve radically new body plans and behaviors. Intercalated tissues can greatly increase the surface area per volume of an organ. Nutrient distribution networks can permit tissues to live surrounded by impervious shells, and support larger organism sizes and volumes. Persistent synaptic learning may be both necessary and sufficient for selforganizing brains. To the extent that Precambrian animal cells are not differentiated in the modern sense, findings in the areas of regeneration and embryogenesis should be interpreted with caution between Precambrian and post-Cambrian animals. For a more technical treatment of these issues, a survey of previous theories on the Cambrian Explosion, and a full bibliography, see (Phoenix 2009), available online. 2 Background 2.1 Stem cells vs. somatic cells Modern animals are built out of many types of cells, with each type locked into its particular function. A neuron will always be a neuron; a blood vessel will never transform into a sweat gland. This fact enables us to have very complex and interpenetrating networks: blood vessels and nerves can extend for meters and exist side by side, and all parts of our bodies can depend on reliable delivery of necessary nutrients and signals. Organs can be constructed of tightly packed structures composed of many different tissue types. In modern animals, a small percentage of cells retain their flexibility, and are called stem cells: they are not yet locked into a single functional role, and they play important roles in tissue generation and healing. Cells that have differentiated into a single functional role are called somatic cells. 1036 2.2 Epigenetics The genetic sequence of a cell does not completely determine its molecular activity; the rate of activity (expression) of each gene also matters. Gene expression can be influenced by chemically modifying either the DNA strand, or the proteins that help to organize the strand (e.g. histones). Methyl group addition, or methylation, is one form of epigenetic modification. Epigenetic modifications date back to bacteria, where they occurred randomly. They may have been useful as “evolutionary tuning knobs,” turning genes on and off over the course of a few generations while preserving fully functional gene sequences. (They may also have helped bacteria to resist viruses.) As multi-generational tuning knobs, epigenetic modifications need to be passed on to each descendant when DNA is copied. Thus, the existence of epigenetic tuning knobs implies that a mechanism for preserving epigenetic information during cellular division must exist, and such mechanisms have been identified in modern animal cells. It might have required only a fairly minor modification of one of these mechanisms to induce targeted epigenetic changes under the influence of chemical signals. 2.3 The Cambrian Explosion The Ediacaran period extended from 630 to 542 million years ago. It began after the last global (or perhaps just near-global) glaciation, and ended with the appearance of modern, complex-bodied, hard-shelled animals. For tens of millions of years, environmental conditions such as atmospheric composition and temperature changed only slowly. Almost all modern animal body plans appeared in just a few million years at the beginning of the Cambrian period. This is called the Cambrian Explosion or Cambrian Radiation. In contrast to the success of animals appearing during the Cambrian Explosion, only a few Precambrian animal lineages, including Cnidarians and Trichoplax, survive to the present day. Previous explanations for this sudden spate of innovation have generally focused on environmental conditions, implying some sort of tipping point that would enable more complex animals, or have postulated some sort of evolutionary feedback or arms race. These explanations rely on rapid results from slowly changing conditions. 2.4 Cellular Differentiation vs. Specialization Differentiation is the process by which cells irreversibly become more specialized. Later in the paper, I argue that cells in Precambrian animals can take on specialized behavior without being irreversibly differentiated, and I refer to this as specialization. Specialized cells would retain their full functional repertoire, being constrained only by ongoing chemical signaling. 2.5 Observations Hydra and Trichoplax have impressive powers of regeneration. Jellyfish can reproduce from a single polyp, and in some (Turritopsis) the adult organism can 1037 revert to a “younger” form which regains the capability to reproduce by budding. All these animals are of Precambrian lineage. The transition from stem cell to somatic cell seems to involve epigenetic changes; in humans, methylation patterns are different in stem and somatic cells. Transformation of a cell to somatic state is generally irreversible without intricate laboratory techniques. Different methylation patterns have been observed between human stem cells and somatic cells. Some jellyfish have highly functional eyes and neural nets, and analogs of modern development-controlling genes such as Hox genes. Jellyfish are not bilaterally symmetrical, and presumably were not the ancestors of modern animals. Thus, it probably was not the development of eyes or neurons or whole-body organization that triggered the Cambrian explosion. 3 Theory 3.1 Setting the Stage Modern animals all seem to share a mechanism for producing differentiated somatic cells. Thus, this mechanism presumably did not develop subsequent to the Cambrian Explosion. On the other hand, the extraordinary flexibility of cells in Precambrian animals suggests that their cells may not be fully differentiated. From a biochemical point of view, differentiation requires a specific mechanism. Epigenetic changes such as methylation are a good candidate for this mechanism. Such a mechanism would have had to be developed via an evolutionary process. In differentiating, a cell gives up its reproductive potential, and cannot survive outside an organism. Thus, from an individual cell’s point of view, a differentiation mechanism is unlikely to develop except in the context of a colony, where differentiation might improve the reproductive success of other cells with the same genes. Thus, the development of differentiation would require successful animals (cooperating colonies of cells) with diversified tissues (so that differentiation would provide a benefit). Since differentiation damages cells’ reproductive potential, there may have been an evolutionary chasm to cross: an animal with differentiated cells would have to quickly gain an advantage to counteract its loss of flexibility of reproductive mechanisms. (Differentiated tissues would have been less capable of self-repair, imposing a further disadvantage.) No longer could a fragment of a damaged animal, or a defecting cell of a dying animal, grow into a new organism to continue the lineage. It is possible that differentiation could only develop and succeed in animals that already had unusually constrained (for the time) reproductive strategies. An analogy might be drawn to the social insects, in which most organisms are genetically locked into roles which do not have any chance of reproduction. Although social insects certainly exist, and lesser examples of self-sacrifice are found all through the animal kingdom, it is rare for animals to evolve such total self-sacrifice. Likewise, it might have been rare for Precambrian cells to evolve mechanisms which would guarantee that they would not be able to reproduce. (They could still divide, but would not be viable if separated from the organism.) In summary, I argue that animals with specialized cells must have pre-dated animals with differentiated cells, and that differentiation may have been unlikely to 1038 develop in any given lineage at any given time, since only unusual animals would have been able to be successful despite the reproductive and regenerative disadvantages. 3.2 Specialization vs. Differentiation A cell that is specialized, but not differentiated - that retains a wide range of potential behaviors and functions - must somehow be informed, at every moment, what its desired behavior is. In the absence of genetic or epigenetic constraint, there must be chemical signaling to tell the cell what kind of cell to be. Maintaining chemical signals imposes a metabolic cost. The metabolic cost of chemical signaling is non-trivial, and would increase as the strength of the signal or the gradient of the signal increased. In other words, a highly reliable signal, or a spatially precise signal, would require significantly more energy. In modern organs, different cell types can exist side-by-side in single-celled layers. This would be difficult and costly to maintain with continuous chemical signaling. Cells capable of differentiation would be able to take on a role in response to a brief burst of precise chemical signaling, and then stay in that role reliably for the rest of the organism’s life. Thus, as little as a few minutes of intense, expensive chemical signaling could specify a kidney or a capillary. Once the cells were somaticized, the organism would be able to count on the proper functioning of each organ without further signaling. A Precambrian animal built of specialized cells might need to maintain a wholebody chemical field, composed of multiple signaling molecules and feedback loops, closely analogous to the morphogen gradients that cause cellular differentiation during embryogenesis in modern animals. If a portion of a Precambrian animal were lost or damaged, the gradients would be distorted, and could reorganize and reprogram the remaining cells to regain functionality according to what was left. This would make it fairly straightforward for a Hydra, for example, to grow new heads after being cut in half. In the extreme, any cause of fragmentation of the organism could be an opportunity for reproduction. On the other hand, fine cellular structures would be lost or distorted during the repair process. A modern animal, with most of its cells irreversibly differentiated, would not be able to reprogram its cells to compensate for damage. Instead, it would have to regrow entirely new tissues to replace the lost ones. On the other hand, any detailed cellular structures that were undamaged would not be distorted during the repair process. 3.3 Of Nerves And Networks Modern animals rely on delicate and far-flung networks of highly evolved cellular function. Capillaries, for example, are lined with layers only one cell thick. Connective tissues are woven throughout the body. Likewise, organs such as kidneys depend on intricate and precisely defined layers of cells. An animal that depends on intricate structures for circulation and separation cannot afford shifts in cellular function in response to changing environments or damage. If a large blood vessel wall were to be disturbed for even a few seconds, the animal would hemorrhage or suffer lack of oxygen in the region served by the vessel. 1039 If the fine structure of organs such as kidneys were maintained by chemical gradients, even a small change in the spatial position of the gradients would render the organs non-functional, perhaps for fatally long intervals. Once cells can be locked irreversibly into particular roles, then organ complexity and function can grow almost without limit. Chemical-processing surfaces can be highly folded into compact shapes. Organs can consist of more types of cells in close proximity. Reliable circulatory systems enable several key advances. Animals can be bigger if they can transport nutrients internally. They can have hard shells without starving the tissues protected by them. And they can support energy-intensive tissues such as muscles. Perhaps the biggest advantage of differentiated cells is in the function of brains. If cellular organization can be disrupted by transient shifts in signaling gradients, then synapses cannot persist reliably. A disrupted synapse can regrow according to its original genetic pattern, but any learning will be lost. Thus, while some jellyfish have quite intricate and useful neural networks, I have been unable to find any reference to jellyfish actually learning. Their neural processing appears to be completely defined and developed by evolution. A brain that can learn is a brain that can implement behaviors far more complex than its genetic specification. To put it another way, a brain that cannot learn cannot self-organize. At least, it would have to learn on a time scale faster than the time scale of disruption, and fast enough to avoid fatal consequences from disorganization. Even quite simple learning - for example, discovering which neurons are adjacent to each other in a distant neural net - would relax the requirement to specify every detail of the neural nets genetically. Self-organizing brains would be less “brittle” to specify; useful function could be retained more easily during evolutionary change. This would allow new brain functionality to evolve much more quickly. And, compared to networks in which every synapse was pre-specified, brains that could adapt to their internal organization, their body, and their environment would be capable of more advanced behaviors under more conditions. 4. Testability and Implications for Research This theory indicates that the Cambrian explosion resulted from a molecular biological innovation in one particular animal. Thus, it predicts that (aside from the possibilities of horizontal gene transfer) all post-Cambrian animals will have a single genetic common ancestor at the beginning of the Explosion. If an evolutionary arms race had been the initial trigger of the Explosion, rather than the result of an immensely powerful innovation, we might expect that multiple animal lineages would have survived. Modern descendants of Precambrian animals may be expected to still be built of stem cells. This would imply the possibility of observing tissue transformation simply by transplanting tissues within the body of an organism. Care should be taken not to transplant tissues large enough to manufacture their own stabilizing signals. Jellyfish neural nets can be quite highly functional, and composed of multiple types of neurons. However, this theory predicts that their function and connection will be the result of continual genetically coded signals, and thus almost entirely 1040 specified by the genome. This has two implications: First, that if disturbed and regenerated, they will be able to reproduce the original functional patterns, probably down to the sub-cellular level; second, that jellyfish will not in general make use of learning. Cnidarians such as Hydra may not be good models for studying regeneration in modern animals. If their tissue cells are effectively stem cells, then we should not expect that their capabilities will tell us much about modern somatic cells. Further elucidation of the molecular mechanisms that somaticize cells in modern animals should shed light on the evolutionary history of those mechanisms. According to the present theory, precursors of those mechanisms may be found in surviving Precambrian lineages, but the full mechanism should not be. 5. Conclusion The Cambrian Explosion has been one of the major puzzles in evolutionary biology, due to its apparent rapidity and lack of apparent cause or trigger. The development of a single biochemical capability - cellular differentiation - could have served as a trigger, and could have fueled extremely rapid expansion of phenotype. Cellular differentiation could have developed from preexisting epigenetic mechanisms, in support of preexisting cellular behaviors, tissue types, and body organizations. Initially, cellular differentiation would have limited the reproductive options of both cells and organisms, so its evolution might plausibly have been delayed for millions of years. But once an animal appeared that could be reproductively successful in spite of these disadvantages, new and highly beneficial structures could begin to evolve. Finely ramified organs, reliable networks, and brains that could self-organize and learn, would all be greatly facilitated by cellular differentiation. All these benefits, arising from one new biochemical capability, could have enabled a rapidly diversifying population of innovative animals, with body types and functions never before feasible. This could easily have driven many of the Precambrian animals into extinction and disrupted the existing ecosystems, opening up further niches for new forms to evolve into. Bibliography [1] Phoenix, C., 2009, Cellular differentiation as a candidate “new technology” for the Cambrian Explosion, Journal of Evolution and Technology 20(2), available at http://jetpress.org/v20/phoenix.htm, accessed May 9, 2011.