Suggested
reading:
[
still under construction ]
- Cognitive
Science:
- Developmental
Biology:
- Modeling
and Systems Biology:
- Bioelectricity:
- Mathematical Biology:
- Biophysics:
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Frequently
Asked Questions (in no particular order)
What
is the weird music on the main page?
It is the
opera version of "Spider Pig", from The
Simpsons
movie (used here in accordance with Title 17 U.S.C. Section
107, distributed without profit.
"Spider
pig, spider pig;
does whatever a spiderpig does; can he swing from a rope? no he can't -
he's a pig."
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
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.
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?
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.
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.
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.
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.
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
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.
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).
Some
things to think about
"Perhaps one day people will interpret the question, 'can you explain it?' as asking 'can you grow it?'"
- Joshua Epstein and Robert Axtell, "Growing Artificial Societies"
"What is number, that man may
know it, and what is man, that he may know a number?" -- Warren
McCulloch
"How
wonderful that we have met
with a paradox. Now we have some hope of making progress." -- Niels
Bohr
"The
man who cannot
occasionally imagine events and conditions of existence that are
contrary to the causal principle as he knows it will never enrich his
science by the addition of a new idea." -- Max Planck
"You
can recognize a pioneer by
the arrows in his back." -- Beverly Rubik
"One
of the methodological
foundations of science lies in the avoidance of
the most fundamental questions. It is characteristic of physics, as
practiced nowadays, not to really ask what matter is, for biology not
to
really ask what life is, and for psychology not to really ask what soul
is." -- C. F. Von Weizsaecker
"The
exact sciences start from
the assumption that in the end, it will always be possible to
understand nature, even in every new field of experience, but that we
may make no a priori assumption as to the meaning of 'understand'." --
Werner Heisenberg
"Tell
me how you are searching
and I will tell you what you are searching for." -- Ludwig Wittgenstein
"It
has always been clear that
we were not so deeply interested in the theory of any particular
biological phenomenon for its own sake, but mainly in so far as it
helps to a greater comprehension of the general character of the
processes that go on in living as contrasted with non-living systems."
-- C. H. Waddington
"Discovery
consists of seeing
what everybody has seen and thinking what nobody has thought." --
Albert von Szent-Gyorgyi
"Information
is information,
neither energy nor matter. No materialism that fails to take account of
this can survive the present day." --Norbert Weiner
Artificial
Life is the study of
man-made systems that exhibit behaviors characteristic of natural
living systems. It complements the traditional biological sciences
concerned with the analysis of living organisms by attempting to
synthesize life-like behaviors within computers and other artificial
media. By extending the empirical foundation upon which biology is
based _beyond_ the carbon-chain life that has evolved on Earth,
Artificial Life can contribute to theoretical biology by locating
life-as-we-know-it within the larger picture of life-as-it-could-be. --
Chris Langton
"Computer
Science is no more
about computers than astronomy is about telescopes." -- E. W. Dijkstra
"Should
one wish to learn the
methods of a conjurer, he might vainly watch the latter's customary
repertoire, and, so long as everything went smoothly, might never
obtain a clue to the mysterious performance, baffled by the precision
of the manipulations and the complexity of the apparatus; if, however,
a single error were made in any part or if a single deviation from the
customary method should force the manipulator along an unaccustomed
path, it would give the investigator an opportunity to obtain a part or
the whole of the secret. Thus. ... it seems likely that through the
study of the abnormal or unusual, some insight may be obtained into
that mystery of mysteries, the development of an organism." -- H. H.
Wilder, 1908
"An unflinching determination to take the whole evidence into account is the only method of preservation against the fluctuating extremes of fashionable opinion.” -- A. N. Whitehead ("Science and the Modern World", Ch. 12).
On
the subject of applied vs.
basic research (e.g., regenerative medicine vs. developmental biology
vs. artificial life):
"The death of
Archimedes by the hands of a Roman soldier is symbolical of a
world-change of the first magnitude: the Greeks, with their love of
abstract science, were superseded in the leadership of the European
world by the practical Romans. The Romans were a great race, but they
were cursed with the sterility which waits upon practicality. They did
not improve upon the knowledge of their forefathers, and all their
advances were confined to the minor technical details of engineering.
They were not dreamers enough to arrive at new points of view, which
could give a more fundamental control over the forces of nature. No
Roman lost his life because he was absorbed in the contemplation of a
mathematical diagram. -- Alfred North Whitehead