The study focused on a fundamental question: how the body tells left from right. Although humans look fairly symmetric on the outside, their inner organs are placed quite asymmetrically; for example, the heart points to the left and the liver lies to the right side.
"We know that in the phase of development, there is a genetic cascade that leads to the proper placement of organs. If that cascade is disrupted, the results can lead to major problems or be fatal," said Salk Professor Juan Carlos Izpisúa Belmonte, who published the findings in the January 8 issue of Nature. Still, scientists did not have a clear understanding of what triggers the genetic cascade that defines organ placement. Izpisúa Belmonte's group focused on the activity of the Notch pathway, an important player during embryo development and also during tumorigenesis, and a key factor for proper left-right asymmetry, as the same group and others had learned earlier this year.
"We knew that Notch activity was necessary for the normal, left-sided expression, but we were clueless as to what was activating Notch preferentially on the left side," said Angel Raya, lead author of the paper. "We examined several factors known to participate early in the establishment of the left-right axis, but none was responsible for what we were seeing."
Izpisúa Belmonte and his team characterized a highly complex chain of events leading to Notch activation, and resorted to mathematics to model the dynamics of this process. The model allowed the team to perform thousands of experiments in the computer (simulations), and pinpoint the factors most likely to regulate Notch activity in the specific fashion seen in the embryo.
"The model pointed in the direction of extracellular calcium, and we were absolutely thrilled when we visualized that, indeed, extracellular calcium accumulated normally on the left side of the embryo. The mathematical model that we developed saved us years of bench work and led to new insights about a biological problem," said Izpisúa Belmonte. "We are very excited about this multidisciplinary approach to biology, and we believe that collaborative approaches between biologists, mathematicians, and physicists working together will lead to long-term breakthroughs in biological research."
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent, nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.