As a child, Eric Wieschaus spent countless hours drawing and painting, and dreaming of becoming an artist when he grew up. Today, this Nobel Prize–winning scientist studies shape, movement, and form—not on canvas but in developing embryos. Using the fruit fly Drosophila as a model, Wieschaus explores the genes that orchestrate the crucial changes in cell size, shape, and position during early embryonic development.
These seemingly subtle changes have dramatic consequences in early embryos, ultimately determining which cells become organs, nerves, muscles, or skin. Based on Wieschaus's research, scientists now suspect that flaws in closely related human genes are responsible for some early miscarriages and congenital birth defects.
"My research has always had a strong visual component, perhaps to satisfy my suppressed desire to be an artist," Wieschaus noted. "I want to understand how cells in the embryo are programmed to form specific structures and how genes control the specialization, or fate, of cells."
Wieschaus was introduced to Drosophila as an undergraduate at Notre Dame, where he found a job preparing fly food in a genetics laboratory. He picked up some basic genetics on the job but was drawn to embryology after taking several courses. Wieschaus was fascinated by the early growth of the fertilized egg, which rapidly divides, or cleaves, to form a hollow ball of 16 cells, all of which look the same. Then, during a process called gastrulation, cells begin to specialize and the embryo becomes asymmetrical, eventually aligning itself along an axis with defined head and tail regions.
"I will never forget the thrill of seeing cleavage and gastrulation for the first time in frog embryos," he said. "I immediately wanted to understand why cells in particular regions of the embryo behaved a certain way and what forces were behind the dramatic rearrangements of cells."
Wieschaus went on to earn a Ph.D. in biology from Yale in 1974, doing part of his thesis work in Switzerland in the University of Basel laboratory of Walter Gehring, a leader in the field of Drosophila genetics and development.
In Switzerland, he met two women who would come to play important roles in his future. One was Trudi Schüpbach, an occasional scientific collaborator with whom he developed a close relationship and later married in 1983. Schüpbach, who studies oogenesis in fruit flies, today is an HHMI investigator and a Princeton University professor. "Our partnership in marriage and in science has played a significant role in my success," Wieschaus notes.
The other was molecular biologist Christiane Nüsslein-Volhard, with whom he began a collaboration in 1978 at the European Molecular Biology Lab in Heidelberg, Germany. Although they were young scientists just embarking on their research careers, the two set out on an ambitious project to find the genes that were essential to transforming a newly fertilized Drosophila egg into an embryo. For this work, they would receive the 1995 Nobel Prize in Medicine or Physiology, an award they shared with Edward B. Lewis at the California Institute of Technology.
No other researchers had attempted to identify these genes, both because of the potentially large number of genes involved and of the uncertainty about how to carry out the research. They decided upon a tedious trial-and-error approach to determine which of the fruit fly's 20,000 genes were absolutely essential to early development. First, the team randomly created mutations in the fruit flies that "knocked out" the function of individual genes. Then, by breeding some 40,000 fly families with defective genes, they studied what went wrong by peering into a microscope fitted with dual eyepieces. Most of the mutations had only minor developmental effects. However, the pair ultimately found 139 genes that proved essential. Without them, fruit flies developed without muscles, eyes, heads, or other vital body parts.
Winning science's top prize has not changed Wieschaus's approach to science. At Princeton University, where he has worked for two decades, Wieschaus still spends a great deal of time at the bench. He has discovered additional genes that control cell fate in Drosophila, and his work now focuses on defining the relationship between cell fate genes and the step-by-step changes in cell shape and form that occur when these genes are activated. Deciphering this process in fruit fly embryos may eventually suggest strategies to counter developmental abnormalities and birth defects in humans.