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(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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(circa 2006) We are not just building four-assed monkeys or Why?

(first posted in my website ~2007)

I am largely motivated by a single, broad assumption of mine: tomorrow’s everyday technologies will be dominated by ‘organic’ machines. In other words, when I dream of the future – 10, 50, 100 years from now – I don’t see hulking metallic monstrosities or sleek mirror-like vehicles or rooms filled with aluminum and plastic. I see machines built from what we would now called ‘living things’: tables that are derived from [what today we would call] plant cell lines, which breathe your office air and use ambient light for energy to fix themselves or grow new parts; houses whose walls are alive and whose infrastructure hosts an ecology [more on ecology below] of organisms who perform tasks both microscopic and macroscopic; computational elements whose interfaces completely blur the line between cell and chip, organ and peripheral.

It is not trivial to defend this notion (nor is this idea at all new). Is there really a reason to do this? (i.e. “Are we just building four-assed monkeys?”). Is it technologically feasible? How would we do it? Even more field-specific: what does all this have to do with microsystems? Isn’t this synthetic biology (yes). Aren’t there ethical considerations?

Developmental biology and machines

Every time a tree or a flea or a human reproduces, a complex program is set in motion that fabricates a new organism. For more than a century, the science of developmental biology has worked to unravel – to reverse engineer—the rules that organisms use to fabricate themselves. Understanding these processes has, of course, led to monumental advances in our quality of life: developmental biology is intimately linked to medicine at all levels.  As we learn what rules neurons use to weave and repair nets or what programs drive muscle repair, this leads to improvements in health care and treatment. The great progress in tissue and organ engineering is fundamentally driven by understanding of developmental biology.

But, beyond medicine, there’s something more fundamental:

[idea 1] there is an underlying fabrication technology that makes nature’s machines and we don’t use it

We don’t make machines the way nature makes them. We do know, for example, how to take whole muscles, or pieces of muscles, or even muscle-precursor cells, form them into muscle-like constructs and graft them onto things to make actuators [see, for example, Bob Dennis’ robot fish[i],[ii]]. But, these grafts are clumsy at best; we certainly do not grow entire machines from scratch that way!

Chemical messages and microtechnology

Developmental biology and its fabrication products are complex. Exactly how cells organize themselves into working tissues, organs, etc. is still the subject of much research and debate. But, I think we have enough information to make one global statement:

[idea 2] cells constantly carry out an internal program which has inputs and outputs to the environment and other cells; this I/O often takes the form of chemical and mechanical signals.

So what? Well, if this is true, we should be able to do two things: a) hack the internal program, b) hack the I/O. The first endeavor has already begun with mostly microbial organisms: it’s called Synthetic Biology. Much of today’s synthetic biology is devoted to designing and building, in what an engineer would call a bottom-up approach, simple gene and metabolic programs into cells. [Imagine finding an alien computer lying in the sand with no user’s manual. After several hundred years of trying to figure out how it works, you now try to build a tiny microcontroller with 10 lines of code with what you’ve learned].

The second endeavor is more closely related to what academics like to call micro or nanotechnology.

[idea 3] we can build generic interface systems with enough spatial and temporal resolution to affect how growing organisms develop.

In other words, I believe that with the right machine we can directly interface with a seed or an embryo (or a completely synthetic lump of cells) as it grows and change the I/O the cells are receiving. I think we can do this with existing organisms [see Essay 1], but I also think we will eventually do this with the completely man-made constructs of synthetic biologists [engineers?]. It is exactly for this reason that my group designs and builds the devices it does: we believe precise control of oxygen, nitric oxide, proteins, etc. during development will eventually allow us to hack the I/O and fabricate new things. [Hopefully not four-assed monkeys come in, although Alphonse Mephisto is such a cool name].

Obviously, the technical challenges are immense. The machines we are building now are very basic and have limitations. Getting messages into and out of cells in real time is daunting and is made more so if you deal with three-dimensional geometries. Reporting on the conditions in the cells is fairly slow at the moment (GFP proteins take ~ 0.3 – 1 hr to fold), although advances are being made rapidly. The developmental programs we want to hack are complex, very redundant and have had millions of years to adapt to environmental insults. This will require the efforts of many people.

You might ask how this all connects to research in other areas which are already co-opting nature’s processes to make wonderful new things. This leads to the last idea of the essay:

[idea 4] a biological cell, as defined by convention and in its many varieties, is the fundamental building block for the proposed technology.

This is not so trivial as it seems. This is what is fundamentally different from efforts which seek to understand biological and biochemical processes in order to employ them outside of the native environment. For me, the cell is the engine of fabrication; it is the basic Lego™ block in the machine’s architecture.

Ethics and ecologies

Ethical considerations can’t be ignored. The ethics of altering living organisms has been raging now for quite some time and many people have written on this. A lot of the groundwork will be laid in the next few years by synthetic biology and its attempts to cope with the issues. But we will not just fundamentally disturb individual organisms. If we do hack the complete fabrication of organisms, our technology will increasingly use the language of nature. It will interface with natural systems more naturally than modern machines do. This is obviously cause for concern, but I think its impact is likely to be positive. Our world is already a host for countless large and small systems of interacting organisms; the study of these systems is known as ecology. If our technology becomes more organic, our man-made systems will begin to merge with these ecologies. Our stewardship of the planet will become more apparent and more direct. In a sense, it will allow us to return to a communion with the earth that has increasingly been lost by the direction our non-organic industrialization has taken. It also means we’ll be able to cause damage and that danger cannot be overstated.