Living World / Sex & Reproduction

For more than 20 years, Van Blerkom has been trying to understand the story that egg cells are telling, and although the tale is far from complete, some compelling new clues to early development have emerged. As both an academic studying the basic biology of mammalian development and as an IVF consultant with access to human egg cells and human embryos for research purposes, he is one of just a few scientists in a position to push a revolution in thinking about how—and whether—life begins. It involves the way an egg cell is built and how information positioned during that construction affects the fate of the embryo.

Scientific study of this phenomenon, known as polarity, could reveal how the fate of a human embryo may be shaped—and predicted—by extremely early biological events that predate conception by days, weeks, or even months. Surprising new research findings by Van Blerkom and others raise the paradoxical possibility that the viability of life may be determined long before fertilization.

The notion of polarity is quite simple. If you imagine the female egg cell (and later, the fertilized egg) as a spherical planet with its own intrinsic biological geography, then certain characteristics of that cell—the location of protein molecules or RNA messages or biochemical traits like pH or even the internal connective structures called microtubules—will be more prominent in certain regions, like one hemisphere as opposed to the other, or near the surface rather than near the core. Polarity of this sort has been known for a long time in the embryological development of simple animals like frogs and fruit flies. For just as long, it was not thought to be relevant to development in mammals.

But in the past few years, prominent British embryologists have shown that polarity exerts tremendous influence on the early development of mouse embryos. And several biologists in this country are pushing the idea of polarity in human development to more extreme conclusions. They argue that the fate of an embryo depends on the way the egg organizes itself, and that polarity in the egg can ordain either a successful or failed pregnancy before conception. This has profound implications for our understanding of life’s origins, for our understanding of why so many embryos spontaneously abort in the first few days after fertilization, and for our understanding of why some IVF procedures may subtly affect early development, with potential long-term health consequences.

Most of all, it means that the scientists who study human development are increasingly looking at deep time, at events that shape the human embryo well before fertilization. The momentum of research, said Van Blerkom, is pushing embryology back into the realm of cell biology, because the fate of the organism is so inextricably tied to the quality of one cell above all: the egg. “In mammals,” he said, “these are things that are too important to be left to chance.” And so they are built into the eggs.

Back in the 17th century, when British physician William Harvey made his famous observation “ex ovo omnia” (“from the egg, everything”), natural philosophers believed that human development derived entirely from the egg. The sperm, in size as well as in deed, was puny by comparison. The most recent research confers molecular respectability upon Harvey’s old maxim. Contrary to the message of 20th-century genetics, the success of the embryo may have less to do with embryonic genes than with maternal proteins passed on by the mother, and less to do with the embryo’s DNA than with the maternal dowry the egg brings to conception.

The basic time course of fertilization and early development has been known for decades. When a sperm cell meets an egg cell (the oocyte), it burrows through the thick outer rind surrounding the egg (the zona pellucida), enters the internal cytoplasm of the egg (the ooplasm), and locomotes its male DNA—half of the typical number of chromosomes—to the female half within about three to four hours. During this microscopic odyssey, the sperm undergoes tumultuous transformations, using some as-yet-unknown materials in the cytoplasm to build a “beacon” to find the female pronucleus, its head of DNA swelling some five times its original size and then later condensing into chromosomes at the end of the journey. “The cytoplasm,” Van Blerkom said, “dictates what the sperm does.”

Once the two packets of DNA meld into one complete set of 46 chromosomes, the one-celled embryo begins to cleave, or divide, becoming a two-celled embryo at around 22 to 28 hours after fertilization, four cells another day later, and eight cells around day three. Only then do the embryo’s own genes fully kick into gear and begin to function. Because these cells are grouped in a loose, pebbly collection resembling a berry, this stage of the embryo is referred to as the morula (from the Latin for “little mulberry”). Around the fourth day, however, the 15-to-25-celled mulberry dramatically tightens and seals its connections with neighboring cells (a process called compaction) and begins pumping fluid into its internal cavity. Now known as a blastocyst, the embryo undergoes a dramatic division of cell fate, forming a distinct outer layer of cells and an equally distinct bulge of about 20 or 30 cells on the inside. The outer cells (the trophectoderm) become the placenta; the inner bulge of cells includes embryonic stem cells, destined to form the entire fetus. Usually by the sixth day after fertilization, the blastocyst will hatch out of the egg cell’s still-resilient rind and attach to the uterus.