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Musings

(circa 2007) Where might we look for inspiration

(first posted on my website ~2007)

(a version of this section appeared, with references, in Ismagilov & Maharbiz, 2007)

Provided with sufficiently advanced interface technology (see also this other Musing), are there existing multicellular systems that can be modified in useful ways? Are existing organisms too complex or lack the plasticity necessary for modification? Among the well-studied developmental biology animal models, including the fruit fly (Drosophila melanogaster), the zebrafish (Danio rerio), the sea urchin (Arbacia punctulata), and the chicken (Gallus gallus), some systems are more amenable to chemical manipulation.  The zebrafish, for example, is transparent, develops around a simple sphere (the yolk), and develops normally even if the impermeable chorion is removed.  However, simpler models may provide even better substrates for building functional biological machines.

Hydra

The millimeter scale Hydra vulgaris and its close relatives are nature’s simplest multicellular organisms possessing a neural net.  A hydra has no central nervous system.  Instead, it has a web of neurons that link chemical and mechanical sensors to primitive musculature, a system sophisticated enough to enable opportunistic feeding on tiny animals wandering into its tentacles. Hydra is much simpler than a mammalian system in a number of ways.  It has two (not three) dermal layers, where the outer skin cells serve as both epithelia and enervated muscle.  The neurons of the hydra can be stimulated locally and globally with simple electrodes.  In addition, the hydra can reproduce by budding. If separated into fragments as small as a few cells, most fragments re-organize themselves into appropriate dermal layers, where cells divide, migrate, and correctly re-form a new hydra in several days. Gradients of chemical signals have long been implicated in establishing and maintaining the hydra’s body plan, and several recent chemical screening efforts have been aimed at identifying putative signaling compounds and their roles. How far could a hydra’s geometry and neuron-musculature be re-patterned by using a microchemical interface device? Are genetic modifications required?  Given recent interest in hybrid metal-muscle devices, the hydra presents an attractive alternative to mammalian muscle constructs.

Volvox and communal algae

Volvox are colonial green algae which assemble into spheroids of tens to thousands of cells. The line between microorganism colony and multicellular organism blurs as one examines the spectrum of Volvox sub-species. In the larger organisms, cells arrange themselves precisely within an extracellular matrix, differentiate into somatic and reproductive cells, collectively locomote towards light, reproduce new spheroids in a coordinated fashion, and are capable of sexual reproduction with other colonies. Moreover, the sex-inducing pheromone of Volvox carceri is one of the most potent signaling compounds known; a 100 aM concentration is sufficient to engage the sexual reproduction pathway. Could Volvox be a template for chemically-modulated self-assembly?  A recent result suggests that extracellular, matrix-mediated self-assembly can be used to form simple multicellular aggregates similar to those seen in Volvox.

Plants

A more immediately useful system may be present in vascular plants. It has long been known that plant vasculature is assembled through a combination of chemical signaling and apoptosis, programmed cell death. The prevailing hypothesis is that the tips of growing plants emit auxin which is transported by downstream cells towards the roots. Cells experiencing the highest auxin concentrations reinforce their walls (with lignin and other compounds), form connections to nearby cells undergoing the same process, and finally commit suicide, leaving networks of empty vessels through which water and nutrients flow. This process remains active into adulthood; if the vasculature is wounded, auxin builds up locally and nearby cells are recruited to form new vascular channels. Exogenously applied, auxin is known to trigger vascular growth towards the source. In this fashion, plants have solved three long-standing engineering problems that still plague modern microfluidic systems: fluidic interconnections across scales ranging from the micro- to the macro- scale (plant vasculature links the smallest leaf capillaries to the largest trunk arteries), the ability to withstand large pressures without generating bubbles through embolism, and high velocity fluid transport without active pumps.

Additionally, a plant’s chemical processing and metabolism is mediated via the vasculature. Lastly, it is a plant’s vasculature in dead form, the secondary xylem, that gives wood its amazing structural range from balsa’s lightness to bamboo’s hardness. Could we co-opt this system to microfabricate vascular networks?

Synthetic constructs

It may be that existing multicellular systems are too complex or too developmentally inflexible for microchemical control of their developmental machinery. For example, microfluidic interface technology has previously been used to show that the development of the Drosophila embryo is robust under the environmental perturbation of a temperature step.  When the two halves of the embryo are maintained at different temperatures, the two halves develop at different rates. Nevertheless, when the temperature step is removed sufficiently early the embryo resynchronizes the two halves and proceeds to develop normally.  Future experiments utilizing microchemical interface technology may enable understanding of the mechanisms responsible for robustness of development and may uncover the limits beyond which developmental programs cannot be perturbed.  If so, the answer may lie in the approaches of synthetic biology. Could we take simple microorganisms, add the right chemical signaling genes, and direct their growth with microchemical interface technology? A recent result demonstrates that prokaryotes can be genetically modified to produce synthetic pattern formation. A number of robust pattern generation systems have been studied for decades, both at the experimental and theoretical level. These include Turing reaction-diffusion systems, simple gradient generators  and chemotaxis models. Could synthetic, addressable pattern generators be inserted into prokaryotes? This is a completely open question.

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