Randall Moon still talks excitedly about the scientific "gift" he received during the 1988 Christmas season. As a recently minted assistant professor at the University of Washington School of Medicine in Seattle, he decided, with collaborator Andrew McMahon (now at Harvard), to investigate what excess amounts of the wnt gene might do to a frog embryo.
Their experiments led to two-headed tadpoles and frogs—quite an unexpected surprise.
Moon's results mimicked those of Hans Spemann, who won the 1935 Nobel Prize in Physiology or Medicine for work that characterized tissue that organized structure formation in an amphibian embryo. When Spemann transplanted tissue from the head of an embryo into another region, the transplanted tissue induced another head to form.
Since Spemann's 1920s work, however, little was known about molecules involved in allowing the embryo to take shape.
In his 1988 experiment, Moon inserted RNA that coded for the Wnt protein into frog embryos, thus increasing the level of Wnt in the cell. The wnt gene, first identified in 1981 as a proto-oncogene causing mammary tumors in the mouse, had been shown to affect the orientation of cells within the fruit fly's embryo. Later in the 1980s, other groups found that wnt belongs to a gene family encoding secreted proteins. But it remained unknown how the protein acted.
Moon's results showed the Wnt protein to be the first known signaling molecule that stimulates the creation of an organizer of the gastrula, a stage in development in which the embryo creates layers—the ectoderm, endoderm, and mesoderm—each of which forms different organ systems and structures in the body. "The experiment was repeated in laboratories throughout the world and really started our careers," Moon said.
Since obtaining his life-changing results, Moon has been dedicated to understanding everything about wnt genes and Wnt proteins, which are highly conserved across species, from the sea squirt to humans. "When animals become multicellular they express Wnts," Moon said. "Wnts are doing something essential for life or else they wouldn't be so prevalent. Evolution doesn't waste its time."
Over the years, Moon's laboratory has not wasted time in unveiling how Wnt proteins influence gene expression, which in turn affects cell growth and development. By binding to receptors on a cell's surface, Wnt proteins activate molecules inside the cell, and that leads to gene activity. In one breakthrough, Moon found that the Wnt signal decreases phosphorylation (or the addition of a phosphate) of a target protein called β-catenin, which then accumulates in the nucleus, where it regulates gene expression.
As Moon and others have revealed, mutations in the Wnt pathway can lead to cancer and changes in bone mass and may have a connection to Alzheimer's. A weakened Wnt signal is involved in a degenerative disease of the retina. Even regeneration, a process whereby damaged or diseased tissue grows back and forms the correct structure, requires or is enhanced by Wnt signaling via β-catenin.
In light of these discoveries, Moon and his collaborators are using Wnt signaling to transform stem cells, or progenitor cells, for cell-based therapies. As director of the University of Washington's Institute of Stem Cell and Regenerative Medicine, established in 2006, Moon sees broad possibilities for clinical applications. Moon's goal, and that of approximately 80 collaborating laboratories at the University of Washington School of Medicine, is to coax stem cells into heart, liver, brain, and other organs to replace diseased cells.
One recent study showed that the Wnt system could be manipulated to increase the number of cardiac muscle cells made from human embryonic stem cell lines. And a mouse model study suggested that Wnts, or drugs that mimic Wnt activity, might be exploited in bone marrow transplantation, which relies on blood cell progenitors to repopulate the bone marrow of cancer patients undergoing chemotherapy or radiation.
Throughout his career—from two-headed tadpoles to cell-based therapies—Moon has taken on techniques, such as proteomics, or animal models, such as frogs, zebrafish, or mice, that were surprising even to him. But as a child of the 1960s, who graduated in 1977 from a "hippie" college, he continues to challenge himself, and conventional wisdom. With his work in Wnts, Moon is following his life's trajectory. "I aim to be different," he said, "and to make a difference."