Mapping the first steps in life
Life begins as a collection of cells, but the journey from that tiny grouping to a fully developed organism is complex and mysterious. Stanislav Shvartsman, a professor of chemical and biological engineering, brings an engineering perspective to studying mechanisms involved in tissue development and form.
In one promising approach, Shvartsman’s lab is using mathematical modeling and experiments on fruit fly embryos to better understand chain reactions of enzymes that control cellular behavior. One enzyme chain currently being studied by Shvartsman’s team, called MAPK, is believed to control the development of structures ranging from compound insect eyes to the mammalian brain. Shvartsman has discovered key mechanisms in cells that affect and are affected by MAPK (mitogen activated protein kinases.)
Enzymes are biological catalysts responsible for all aspects of life. Most, but not all, are proteins. Our understanding of enzymes dates back to an experiment done one hundred years ago, said Shvartsman, who is also a professor the Lewis Sigler Institute for Integrative Genomics. In that experiment, Leonor Michaelis and Maud Menten analyzed how an enzyme called invertase breaks down sucrose, a two-ring sugar.
“One hundred years ago, they came up with a beautiful description of a very simple system – one compound being converted into one product,” said Alan Futran, a graduate student who works with Shvartsman and Professor A. James Link. “Now the challenge is putting that initial insight into a much broader context.”
Enzymes in cells do not function in isolation, but work as parts of complex networks, which act as control systems for processes such as cell growth and differentiation.
“We have many different enzymes,” Futran said. “And they are often buried in these very big networks.”
One of the projects the researchers are pursuing involves the MAPK enzyme chain (which was originally called ERK for extracellular signal-related kinase, and pronounced “erk.”). This enzyme pathway has hundreds of substrates, chemicals that are acted upon by the enzymes.
MAPK is active from the earliest stages of embryogenesis, when it is involved in putting together tissues and organs. In the adult organism, MAPK is involved in tissue repair and maintenance.
MAPK is not only used throughout the lifetime of the organism, but it is also used across species. In fact, structures as diverse as compound insect eyes and highly folded mammalian cortex form under stringent control of MAPK.
This conservation is a key to the experimental approach of the Shvartsman lab, which uses the fruit fly, a model organism of developmental genetics, to study the general principles of MAPK regulation and function.
The levels of MAPK activity must be tightly controlled. Reduced levels of MAPK activation in the embryo can lead to developmental disorders, such as congenital heart defects. Excessive MAPK activity in the adult tissue can cause the creation of tumors.
Futran said that researchers can experimentally test conditions that alter the MAPK pathway, for example changing the level of substrates. But because of the complexity of the pathway, and its involvement in different processes, it can be hard to determine exactly how those changes play out inside a cell.
“If you change the level of one ERK substrate, it can affect the activity of other substrates,” he said. That makes it hard to determine whether the first substrate, or another secondary substrate, caused the change to the cell. This complexity means that researchers often rely on mathematical models to explore potential patterns in the enzymatic cascades.
“Of course, no model is perfect, but by going back and forth between modeling and experiments, and experiments and modeling, we can get a better understanding of enzyme networks” Futran said.
Shvarstman said there “is still much to learn but our understanding of these very complex systems is growing steadily,” he said. “It is a very exciting time.”