June 4, 2007 -- The development of the human embryo is exquisitely choreographed. After fertilization, the egg starts dividing. After four rounds of division, the embryo, now known as the morula, leaves the fallopian tube and enters the uterine cavity. As it moves, the morula changes form. It starts to resemble a microscopic tennis ball, inside of which are a hollow space and a mass of cells. The cells inside the ball form the embryoblasts, while those on the outside become trophoblasts, cells that will form the placenta.
After about a week, the embryo embarks on a critical stage in its development: it implants itself in the uterine wall. This process requires a complex exchange of signals — in this case between the trophoblasts and the uterine lining — that must occur in a precise sequence. Ann Sutherland, an associate professor of cell biology, is trying to unravel this cellular dialogue. “In humans, the ability of embryos to implant in the uterus is regulated tightly,” she says. “There is a short window of uterine receptivity. The embryo has to be ready to implant when the uterus is ready to receive it.” Sutherland’s research has important implications for our knowledge of infertility.
Sutherland knew that the presence of two amino acids — leucine and arginine — played a critical role in preparing the trophoblasts, but she wasn’t sure how this process worked. A lecture given by John Lawrence, the late professor of pharmacology, provided an important clue to the missing link. Lawrence studied a cell-signaling pathway regulated by a protein called mTOR (mammalian target of rapamycin), part of a class of molecules called kinases. Although Lawrence was principally concerned with the relationship of mTOR and insulin, his work struck a chord with Sutherland because mTOR is regulated by leucine and arginine. “The amino acids regulate mTOR in the embryo, which triggers the transformation of the trophoblasts from a passive to an active state,” Sutherland says.
For scientists, one answer suggests a host of questions. Armed with two parts of the mechanism that prepares embryos for implantation, Sutherland is searching for the rest. She wants to know how the amino acids stimulate the mTOR signaling cascade. She hypothesizes that nitric oxide, a biological messenger molecule produced by arginine, might be the missing link — and it would have the additional advantage of encouraging capillary growth in the uterus, making it more receptive. She is also interested in finding out how the trophoblasts become aware of the amino acids in their environment.
This entire line of research represents a departure for Sutherland, who had been focusing on a different aspect of implantation. She had been studying the role played by the extracellular matrix — a layer of specialized molecules that develops between cells — in the differentiation of embryo cells into embryoblasts and trophoblasts and in the embryo’s implantation into the uterus.
Sutherland, however, is excited by the new turn her research has taken. “If you are too focused, you may be missing something,” she says. “When a doorway in your research opens, you have to step inside.”