Frequently Asked Questions

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To see how our views have evolved over the years, here are our answers to frequently asked questions in 2012.

1. What does your lab work on?
2. What ties it all together?
3. What are some of the Big Questions you are addressing?
4. What makes symmetry a Big Question?
5. Why do you work on so many things? Why not focus?
6. What's all this bioelectric stuff? What is bioelectricity and why not stick to well-known biochemical signals?
7. If ion channel properties set up the initial conditions for the voltage gradient dynamics, aren't they ultimately the driver, and the key thing on which selection operates?
8. Which model systems do you use and why?
9. What techniques are used in the lab?
10. Why are all the projects so unusual and the emphasis different from most of the mainstream work in the field?
11. What are the practical implications of your work?
12. Who else does this kind of work?

1. What does your lab work on?

Projects include:

• Understanding the role of cytoskeleton in the initiation of left-right asymmetry
• Understanding the role of ion channels/pumps in establishing bioelectric gradients during early left-right patterning
• Understanding how physiological gradients become transduced into asymmetric patterns of gene expression
• Understanding the role of specific ion currents in limb, tail, and craniofacial regeneration
• Learning to control bioelectric state of wound cells to promote regeneration of limbs, eyes, and other complex structures
• Understanding the role of brain and body asymmetry in non-lateralized behaviors (intelligence, recall, etc.)
• Understanding how bioelectric circuits control anatomical polarity and morphogenesis during planaria regeneration
• Analyzing the ability of tissues and cells outside the CNS to remember information and imprint it on the regenerating brain
• Understanding the bioelectric signatures (and control modalities) for neoplastic transformation (cancer)
• Understanding neurotransmitter and transmembrane potental control of stem cells by the host during morphogenesis
• Developing automated learning systems to allow high-throughput search for nootropic compounds
• Developing computational modelling tools for a bioinformatics of shape
• Developing models of self-generated order and information storage in physiological networks

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2. What ties it all together?

We view biological systems from a cybernetic perspective: how do living structures acquire, store, and process information? Information comes in two flavors: spatial (morphological) and temporal (patterns in environmental signals). We address the former by asking how large-scale pattern formation is established, maintained, and regenerated against perturbations. We address the latter by asking how memories (learned information) are stored and transmitted by different types of biological structures.

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3. What are some of the Big Questions you are addressing?

• How is consistent left-right asymmetry leveraged from subcellular (molecular) chirality onto multiple cell fields?
• How do organisms store the "target morphology" to which they repair during regeneration and morphostasis?
• Can cancer be understood as a disease of geometry (failure to attend to large-scale morphogenetic cues of the host)?
• How can we generate quantitative algorithmic models that go beyond pathways and allow us to predict (and rationally manipulate) shape?
• How are adult stem cells integrated into complex morphogenetic activity by the host context (3D patterning, beyond stem cell differentiation)?
• How are bioelectrical signals used to establish long-range patterning cues and how are these signals linked to transcription networks and biochemical pathways?
• What aspect of cellular function enables memory and what is the relationship between information processing and its tissue substratum?
• How can the real-time dynamics of physiological networks generate and store patterning information?
• Can non-neural tissues support computation, and how does brain plasticity make sue of morphogenetic lability?
• Do developmental mechanisms encode adaptive, intelligent algorithms that are best described using techniques of cognitive science?

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4. What makes symmetry a Big Question?

Symmetry is "immunity to a possible change". As such, it is fundamental to reproducibility, predictability, reduction, gauge symmetries in physics, and much more.

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5. Why do you work on so many things? Why not focus?

These are the questions that keep me up at night! As long as we're making progress, and no other lab is addressing the same workplan, we continue to push all of these fascinating directions. They seem to cover very different aspects of biology, but there may be fundamental connecting features underlying them all and that is the hypothesis that drives all of this work.

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6. What's all this bioelectric stuff? What is bioelectricity and why not stick to well-known biochemical signals?

Bioelectricity refers to signals carried by the voltage gradients, ion flows, and electric fields that all cells receive and emit. It has been known for over 100 years that all cells, not just excitable nerves and muscle, exhibit steady-state long-term bioelectrical activity, and that this activity appears to be instructive for cell guidance, wound healing, and regeneration. It has been abundantly show that these signals are not mere housekeeping physiology, but indeed serve to control proliferation, migration, and differentiation of cells. Although an increasing number of microarray and other unbiased approaches have been turning up ion channels in such roles, the function of specific ion transport events in morphogenesis in vivo has only been scratched at the surface. The latest challenge has been to use the high-resolution powerful tools of molecular genetics to probe the functional roles of bioelectric signals in regeneration, development, and cancer and show how these signals integrate with the biochemical and genetic pathways familiar to modern cell biology. We are fascinated by these signals because 1) they offer very different properties for use in morphogenesis than do chemical gradients, 2) they function as a biophysical epigenetic layer on top of well-studied pathways, 3) they often act as master regulators, inducing complex morphogenetic programs from relatively simple signals, and 4) they appear to be widely conserved as patterning signals and thus offer great opportunity as control points for regenerative medicine.

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7. If ion channel properties set up the initial conditions for the voltage gradient dynamics, aren't they ultimately the driver, and the key thing on which selection operates?

First, channels open and close post-translationally, which means that (just like in the brain), a bioelectric network has its own intrinsic dynamics that do not require pre-existing chemical/genetic pre patterns. Second, because some ion channels are themselves voltage-sensitive, this makes for feedback loops: networks of cells expressing these can exhibit symmetry breaking and self-organization of voltage distributions without pre-existing transcriptional or protein-level differences. Finally, there are *many* different channels that can give rise to the same voltage. This means, the underlying ion channel loci are actually fairly free to diverge evolutionarily (in terms of promoters, or mutations of actually channel structure) as long as they are replaced by variants that support the same (or very similar) Vmem distribution - it's the Vmem pattern (and its dynamics in space and time) that regulate morphogenesis and function, which is ultimately acted up on by selection. This is a nice example of "multiple realizability", where numerous gene products can drive the same function. In this sense, resting potential is like "pressure" or "temperature" - a functionally useful coarse-graining that abstracts from the underlying details (gene identity of each channel). As with pressure, Vmem is the right control point for building things - you don't want to try to manage each atom in a steam boiler, you want to manage the pressure. We know voltage distributions are instructive (causal) because by regulating this (using any convenient channel), we can induce appropriate functional patterning outcomes. One way to view this work is that we are looking for a version of statistical mechanics for bioelectricity - cracking the bioelectric code by identifying useful laws that function above the level of individual gene products.

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8. Which model systems do you use and why?

• We use Xenopus laevis embryos because they're ideal for physiological experiments and are amenable from the earliest stages of development.
• We use zebrafish because they are transparent, and offer transgenic technology as well as optical techniques in a rapidly-developing organism.
• We use chick embryos because their flat early blastoderm is a good model for most amniotes (including mammals) and are very accessible in ovo.
• We use planaria because they possess incredible regenerative ability, are smart (can learn, allowing memory and brain regeneration experiments in the same animal), and are a convenient system in which adult stem cell integration into morphogenetic events can be studied.

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9. What techniques are used in the lab?

• Standard molecular biology - cloning, qPCR
• Developmental genetics - expression analysis, transgenesis, regeneration assays, pharmacological screens
• Cell Biology and biophysics - cell and tissue culture
• Biophysics and physiology -in vivo analysis of bioelectrical state via fluorescent reporter dyes
• Behavior analysis - automated, quantitative, parallelized training and tracking of model animals
• Mathematical modeling - computer simulation, symbolic model generation

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10. Why are all the projects so unusual and the emphasis different from most of the mainstream work in the field?

I am, fundamentally (and by training), a computer scientist and I suppose that's why my perspective on these questions is different.

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11. What are the practical implications of your work?

Our projects are basic research aimed at understanding fundamental mechanisms. However, once uncovered, these mechanisms suggest control points for biomedical intervention. Thus, our work suggests novel approaches to the detection, prevention, and repair of birth defects (especially involving the laterality of the heart and various internal organs), new diagnostic and treatment modalities for some types of cancers, approaches to induce regenerative repair of limbs, eyes, spinal cords, and face, and the discovery of new nootropic drugs (compounds that increase intelligence or improve memory for example).

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12. Who else does this kind of work?

My lab (and our post-docs who have gone on to independent positions) are pretty much the only ones that specifically focus on bioelectrical signaling per se, in vivo, in complex pattern regulation. However, there are many people working on other aspects of this field broadly. For example, several labs to state-of-the-art molecular work on electric fields in wound healing and cell responses to electric fields, including Min Zhao, Colin McCaig, and Sylvia Chifflet. Many bioengineers use applied electric fields to control cell behavior in vitro, and cell biologists study voltage gradients in cellular polarity, such as the elegant recent work of Mathias Simons. Moreover, numerous channelopathies (e.g., Andersen-Tawil and Angelman syndromes) involve patterning defects - anyone who studies the molecular medicine of these birth defects is, in effect, working in developmental bioelectricity. For example, Emily Bates is performing molecular studies on the role of potassium channels in BMP signaling and developmental patterning. Also, there are a number of people who are characterizing specific patterning mutants which turn out to be mutations in ion channels, such as this nice story on size control in zebrafish; thus, straightforward genetic approaches can lead one into a bioelectric project. Finally, there are also labs studying ion channels in cancer, which is also a bona-fide example of non-neural bioelectricity in cell regulation.

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