Living World / Sex & Reproduction

While the debate over polarity is much more sophisticated these days, it is not entirely new. In the late 1930s and 1940s, Arthur Hertig, John Rock, and several colleagues did an experiment in human embryology that to this day remains without peer in terms of elegance, revelation, and chutzpah. Working at the time as a researcher at the Free Hospital for Women in Brookline, Massachusetts, Hertig persuaded eight women scheduled to have hysterectomies to record intimate details of their lives prior to the surgery to remove their wombs, including when they menstruated and had sex. Armed with such precise information, Hertig’s research team found developing embryos in either the fallopian tubes or uteruses of the women and, adapting the headlight from an automobile to illuminate their work, took photographs of early, preimplantation human embryos. Not only were they able to estimate when fertilization had occurred and also plot the time course of early human development, they also made an astonishing discovery: Half the embryos were clearly abnormal. This was the first concrete hint that most human embryos fail during the first week of development. Among other things, the paper that Hertig and Rock published in 1954 contained some of the first micrograph images of a human embryo at the two-celled stage. Hertig expressed the hunch that one of those cells was destined to be placenta, the other the developing organism.

Throughout his distinguished career (he headed the department of pathology at Harvard Medical School for two decades), Hertig suspected that there was a very early commitment by embryonic cells to become either a fetus or the placenta. He continued to explore this idea after his retirement, when Harvard set him up in an animal laboratory in the central Massachusetts town of Southborough to continue embryological research in monkeys. In the mid-1960s, the lab hired a teenager from nearby Hudson for a summer job cleaning out animal cages, and Hertig filled the kid’s ears with his theories. “I had no idea who this guy was,” the teenager would later say. “But he took me under his wing, and by the end of the summer, the guy is teaching me about ovaries and eggs.”

A print of that first micrograph of a two-celled human embryo is now framed and hangs on the wall above the desk in David Albertini’s small, crowded office at Tufts University where, 30 years after he cleaned the monkey cages in Southborough, he conducts research trying to figure out how the fate of those two cells is determined. The search keeps leading back to the mother’s eggs. “You can’t produce a healthy human unless you produce a healthy egg,” said Albertini. “What endows a healthy egg, and thus a healthy embryo?”

In some respects, a human egg takes a lifetime to mature. Each female possesses up to 2 million oocytes at the time of birth, but that number is winnowed down to about 250,000 by puberty. Roughly 400 of these unfinished oocytes will mature and be ovulated during a woman’s reproductive years, although the quality of the finished eggs declines as she ages. The vast repository of egg cells remains shelved in the follicles until the brain sends a signal in the form of monthly bursts of hormones, which trigger the final maturation cycle. From that signal, it takes approximately 110 days for an egg to grow, mature, and finally be released from the follicle.

In the late 1980s, Albertini’s group began to focus on a group of satellite cells that surround the oocyte as it begins to grow and mature in the follicle. As eggs develop, each one is surrounded by a herd of much smaller hangers-on. These are called granulosa cells, and under the microscope they look like grapes glued to a beach ball. Albertini and his colleagues noticed that the interaction between the oocyte and the cells surrounding it was not symmetrical; there were more cells—and, it would turn out, more molecular back-and-forth traffic between the egg and the granulosa cells—at certain regions on the egg.

“We proposed that these cells on the outside were imposing an asymmetry on the egg,” Albertini said. The pattern, originally identified in rodents, has now been shown to be true of cows, rhesus monkeys, and as of three years ago, humans. “Almost all animals build an egg in the ovary and position molecules in the top and bottom. This is a highly conserved evolutionary mechanism to make sure that when the cell gets subdivided, the cells at the top will become the head, for example, and the cells in the back may become a gonad. So you basically have to lay that down in the egg. And then you’re just carving up the pie. We’ve been the first to have evidence to support that in the mammal, though not in the human yet. And there is evidence in human eggs, from Van Blerkom and others, that molecules are partitioned.”

Unlike Van Blerkom, who has regular access to human eggs and embryos through his IVF-related work, Albertini works primarily with mouse and primate cells. But his lab’s animal studies have revealed that asymmetry in an immature egg is important to the development of an embryo.

Through a series of elaborate experiments with mice, Albertini and his colleagues at Tufts have shown that the small cells bunched around an egg cell in the follicles are not mere microscopic groupies. They form connections, known as gap junctions, that send tendrils much like plumbing lines into the egg. The plumbing analogy is apt because molecules flow into and out of the egg through these channels. The molecules are critical to normal development: When the genes for certain of these molecules are experimentally erased, the eggs made by female mice are invariably defective, and the errors fatally disrupt the normal choreography of egg maturation.

Moreover, Albertini’s group is exploring whether these plumbing lines, which corkscrew into the outer rind of the egg, play a role in establishing one of the most important geographic landmarks in the life of an egg cell—an event, Albertini likes to say when lecturing medical students, that marks “one of the most important days in your life.”