Cell communication

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 biology.

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 surfaces.

Autocrine system

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 cells' behavior.

"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.

Self-control

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 equations.

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 they produce.

Complex models

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 autocrine loops.

"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.

Work together

"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 is associated.

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 said.

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.