fruit flies hold the key to understanding?
by Carrie Lock
No pests are more bothersome than the uninvited fruit flies
that seemingly find their way to every summer picnic. You
may think you know these creatures all too intimately, but
you might want to consult an expert.
For almost a century fruit flies have been helping scientists
answer basic questions about life. In 1910 Thomas Hunt Morgan
used the common fruit fly, Drosophila melanogaster,
to test the chromosomal theory of heredity. In the years since,
the fruit fly has become an important tool for studying developmental
looking at these things in the place biologically, where
the system operates in tissues."
Professor Stanislav Shvartsman
Stanislav Shvartsman *99, assistant professor of chemical
engineering, is using Drosophila to study how cells
communicate with one another.
During Drosophila's embryonic development, a thin
uniform layer of cells called the epithelium, initially covers
the egg. At some point these cells become "patterned."
Two regions start to look much different from the rest. Eventually,
these regions grow into dorsal appendages, a pair of organs
responsible for delivering oxygen to the developing embryo.
How these patterns form may be the key to understanding cellular
communication--in both flies and humans.
Over the last 20 years scientists have painstakingly worked
out the molecular mechanism of dorsal-ventral patterning.
The nucleus of the egg moves closer to the epithelial layer,
to the location where the patterning eventually begins, and
produces a peptide called Gurken.
This ligand binds to and activates growth factor receptors
(EGFR) located on the surface of the epithelial cells. The
Gurken-EGFR complex induces a cascade of intracellular events,
including the production and secretion of another ligand called
Spitz. Spitz can then bind to EGFR on the surface of the same
cell or diffuse away to neighboring cells and bind on their
This is an autocrine system, which occurs when the secretions
of a cell can stimulate the cell itself. This type of mechanism
acts as a positive feedback loop, amplifying the initial signal
and extending it to nearby cells.
In the epithelial cells near the original release of Gurken,
the levels of EGFR activation are much higher than in their
neighbors. These cells express an additional player, Argos,
which acts as a negative regulator.
Argos also binds to EGFR, but inhibits the cascade of events
induced by the ligands Gurken and Spitz, thereby slowing down
or even halting their production. Argos serves to "split"
the chemical signal into two spatially separate domains, which
eventually become the two dorsal appendages in Drosophila.
"This system of patterning is really conserved from
mice to men, from worms to flies, and this is really amazing,"
Professor Shvartsman said. "They are the same molecules
and the same parts that are used in different organisms for
many different functions."
Two scientists at Cambridge University proposed this basic
mechanism in 1998, but it was Professor Shvartsman who developed
a complex mathematical model that successfully captures the
"The way it was studied traditionally was in vivo,"
Professor Shvartsman said. "The interaction of this peptide
with this receptor was studied, or the response of a single
cell to this peptide was studied, and in some cases even modeled.
The main difference in what we're doing is that we're looking
at these things in the place biologically where the system
operates, in tissues." His model of cell signaling combines
all the traditional elements of chemical engineering--reaction
engineering, fluid-phase transport, and process control--to
model a biological system.
The binding of ligands to receptors, for example, is described
with rate constants in the same manner as simple chemical
reactions. Brownian motion and diffusion describe the movements
of the ligands in extracellular space.
The concentrations of Spitz and Argos control their own production
in positive and negative feedback loops. All of the equations
describing the model are solved by numerical analysis of differential
By changing some parameters in his model, such as the strength
of the initial Gurken signal, Professor Shvartsman is able
to predict some naturally occurring mutant forms of Drosophila.
For example, he can generate model flies with zero, one,
three, or four dorsal appendages. This begins to connect the
expression of specific genetic mutations to the abnormal phenotypes
Professor Shvartsman's models of cell-signaling networks
are becoming more complex with the addition of a more detailed
description of the transcription and expression of specific
genes. In addition, he wants to add cell motility to the list
of phenomena his models describe.
Cell motility, or movement, induces changes in the form and
structure of tissues. He said that in the next few years "we
would be very interested in getting quantitative imaging of
cell motility induced by changes in gene expression induced
by receptor-mediated processes induced by cell communication.
We could look at the generation of biological form directly
by looking at migrations, but this is very far."
Professor Shvartsman earned his Ph.D. from Princeton, where
he studied catalysis and reaction engineering under Professor
Yannis Kevrekidis. How did he make the leap from an
established chemical engineering field to developmental biology?
He first became interested in cell-signaling networks at
a conference where Doug Lauffenburger, a professor from the
Massachusetts Institute of Technology (MIT), gave a talk about
"And I went to a seminar [at Princeton] by Howard Berg
from Harvard," Professor Shvartsman said. "He was
talking about bacterial chemotaxis, and the talk was just
beautiful. Everything from fluid mechanics to controls, optics
to bacteria--it was very exciting."
While he was still a graduate student at Princeton, he took
a class in the molecular biology department on signal transduction
in cells. He eventually became a postdoctoral associate at
MIT under Professor Lauffenburger.
"It's impossible for an engineer to work on these systems
and not feel incompetent every second because there is so
much you don't know," Professor Shvartsman said. "You
don't know genetics, you don't know cell biology. You really
depend on brave students to decide that this is beautiful
and doable for an engineer."
Currently he has assembled a young team of graduate students
to pursue this research, and they do so with as much passion
as he does.
"One thing I try to encourage is my students working
together," he said. "Everybody has their strength,
but if you think about the patterns in research now, many
more things are becoming collaborative."
This fits in with the ideals of the newly built Lewis-Sigler
Institute of Integrative Genomics, wi th which Professor Shvartsman
The building was specifically designed to facilitate interdisciplinary
cooperation among the wide varieties of scientists who work
within its walls.
"In this way, you don't have to buy your own -80°
freezer, which costs a lot of money," Professor Shvartsman
He incorporates his interdisciplinary ideas in a course called
"Computational Biology of Cell Signaling Networks,"
which is cross-listed in the molecular biology, chemical engineering,
and applied mathematics departments.
In addition, Professor Shvartsman teaches the graduate-level
reaction engineering class in chemical engineering. Finding
ways to bridge the fundamental with the nontraditional are
themes that express themselves in all aspects of Professor
Shvartsman's intellectual life.
"We understand how to manipulate semiconductors and
we have a laser," he said. "We understand how to
manipulate polymers and we have a coating. But if you want
to manipulate anything that is life, you first need an understanding
of how tissue is held together and what it depends on."
And you thought the flies were just there for the food.
Carrie Lock *03 recently received her master's of science
degree in engineering from Princeton, and she is now in Boston,
where she is pursuing a master's degree in journalism at the
Center for Science and Medical Journalism at Boston University.
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