Specialized cells have a common origin. What sets them on separate paths?

by Liza Gross

More than two thousand years ago, the Greek philosopher Aristotle first proposed that animals develop gradually in size, shape, and complexity. He based his theory on what he observed when he dissected chick embryos. But despite Aristotle’s findings, his peers believed that animals were fully formed from the earliest stage of embryonic development. As late as the seventeenth century, some scientists thought a person appeared inside an egg or sperm cell as a tiny but fully developed human, the homunculus, and simply grew.

By the nineteenth century, embryologists recognized that a fertilized egg develops according to an exacting schedule, pattern, and plan. It does not harbor a fully formed human, but it has the potential to build one. That potential, we now know, comes from a class of cells called stem cells. Stem cells have two features that make them unlike any other cell: They can make identical copies of themselves, and they can make differentiated—specialized—cells such as nerve cells or muscle cells.

Though most stem cells will ultimately meet separate fates, the biomechanisms that control their destinies are largely the same. Master genes coordinate a complex network of molecular, genetic, and cellular signals that tell each cell what role it will play in constructing a human being. These master genes act as developmental regulators, directing specific sets of genes to make specific proteins. Once a cell gets the signal to make a protein specific to a particular type of cell, such as a muscle cell, it has committed to becoming that type of cell.

From One to Many

Fertilized egg When sperm and egg fuse during fertilization, the genes of father and mother combine to form the full complement of a human’s thirty thousand or so genes, or genome. The fertilized egg creates not just the embryo but the tissues needed to support it. About twenty-four hours after fertilization, the egg divides in two. With every subsequent division, a complete copy of the genome gets passed on to each new cell, but only some of these genes will be used in any one cell at any given time and place. Morula After about seventy-two hours, the embryo forms a solid ball of cells called the morula. That’s when the cells part ways: Some move to create an outer rim; some remain in the interior. Next, a fluid-filled cavity forms inside the morula, and the interior cells secrete proteins that turn the morula into a blastocyst, which implants itself into the lining of the mother’s uterus. Blastocyst The outer cells of the blastocyst contribute to the placenta, as does the uterine lining. The inner cells are stem cells that will spawn the more than two hundred types of cells that make up the human body. As the cells inside the blastocyst continue to divide, they undergo gastrulation, arranging themselves in three layers to form a gastrula. These three cell layers—ectoderm (outer), mesoderm (middle), and endoderm (inner)—produce all the body’s tissues, organs, and systems. The nervous system and outer layers of the skin, for example, come from ectoderm cells; heart, kidney, bones, and muscles from mesoderm cells; and lungs, liver, and pancreas from the endoderm.

Stem cells also respond to signals from their neighbors, which tell them to activate genes that make proteins controlling how they will move, differentiate, and adhere to other cells to build tissues. Over the course of embryonic development, different sets of genes will be retired and others called to duty in the service of transforming these amorphous stem cells into single-minded specialists.

There are two kinds of stem cells —embryonic and adult. Embryonic stem cells have the potential to become any type of cell except those that form the placenta,umbilical cord, and other embryo-supporting tissues. Discovering the molecular signals that orchestrate embryonic stem-cell differentiation will provide fundamental insights into the key mechanisms of cell division and early development. This knowledge will also lead to methods of intervening when something goes wrong.

Adult stem cells are unspecialized cells that live in specialized tissue, such as epithelial tissue in the skin. Their job is to produce cells that maintain and repair that particular tissue through- out an individual’s life. Adult stem cells are hard to find and difficult to identify. Fewer than one in ten thousand bone marrow cells, for example, is a blood-forming stem cell.

Because many diseases and birth defects arise when corrupted genes disrupt the normal operations of healthy cells, many scientists are focusing on therapies that replace damaged cells with healthy cells. Embryonic stem cells offer enormous therapeutic potential for a range of genetic and cell-based illnesses, such as cancer and Parkinson’s disease, because they can generate so many different types of cells. And because these cells can make identical copies of themselves for extended periods in the lab, researchers can produce the huge numbers required for medical therapies. The embryonic stem cells typically used in this type of medical research come from five-day-old embryos, which have about two hundred to two hundred and fifty cells. Most of these embryos are donated to research institutions by clients of in-vitro fertilization clinics.

Until recently, scientists thought adult stem cells existed only in tissues and organs that required constant replacement, such as skin, blood, and the lining of the gut, and that they could produce only the cell types of their particular tissue. But adult stem cells are turning up in unexpected places, including the brain, and recent studies suggest that they may be more versatile than once thought.

When researchers at the University of Florida injected the coronary arteries of a mouse with adult stem cells extracted from the skeletal muscles of human volunteers, the human stem cells differentiated into mouse heart cells. And researchers working with mice at Cold Spring Harbor Laboratory in New York have persuaded adult stem cells found in the nervous system to become skeletal muscle cells.

But not all adult stem cells respond to researchers’ attempts to nudge them in different directions. Cell differentiation most likely depends on activating a specific set of genes, and forming the appropriate types of proteins; finding the right combination of genes and proteins is a monumental task. It’s also unclear how long these adult cells will self-renew. That’s why embryonic stem cells still seem to offer greater therapeutic potential: They have been seen to proliferate for more than a year in the laboratory and can give rise to a wider variety of cell types.

Though we’ve been looking at stem-cell differentiation in humans, the genetic and molecular pathways are similar in most sexually reproducing animal species. And as researchers enlist more and more organisms in their search for the biochemical underpinnings of development, they’re finding the same processes in species after species.

Looking at organisms as diverse as worms, flies, and humans, researchers at Massachusetts General Hospital and Harvard Medical School found the same gene regulating the timing of key developmental stages in each one. This suggests that the gene evolved nearly a billion years ago (with the first animal, a spongelike creature) and was inherited by nearly all subsequent animal species.

The presence of this and many other regulatory genes in so many different animals suggests that the mechanisms of animal development are universal. Like so much of biology, every discovery peels back the apparent difference among species to reveal an underlying unity.

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This story originally appeared in the Cells issue of the "Exploratorium Magazine."

CREDITS: Micrographs by Kristina Yu, Microscope Imaging Station, © Exploratorium, using a Zeiss 200m Axiovert and Metamorph software under a grant supported by the National institutes of Health and the David and Lucille Packard Foundation. Illustrations by Gary Crounse.

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