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In Tiny Cells, Glimpses of Body's Master Plan

December 18, 2001

The human body looks and works like a seamless whole, but it is constructed of individual units too small to be seen, some 100 trillion living cells. The designer of the body is evolution, but its builders are the cells themselves. They proliferate from a single egg, morph into at least 260 different types and spontaneously organize into a perfectly integrated system of organs and tissues.

Biologists only dimly grasp the principles of this extraordinary self-assembly, but they are quickly learning the habits of its principal actors, a special class of cell known as stem cells. One kind of master stem cell generates the infant from the fertilized egg and then, its living sculpture completed, disappears. A class of maintenance stem cells then assumes the duties of replenishing and repairing the body throughout the owner's lifetime. The fleeting creators, known as embryonic stem cells, generate every tissue of the body, but their successors, the adult stem cells, are generally limited in scope to making a single kind of tissue.

Stem cells have recently burst from the obscurity of the research laboratory into the arena of national politics, propelled by assertions that they are either the fruits of murder or the panacea for the degenerative diseases of age. Obtained from the surplus embryos generated in fertility clinics, human embryonic stem cells have not yet been much studied because many biomedical researchers those supported by federal grants were forbidden to work on them until President Bush's decision on Aug. 9 to allow research with embryonic cell cultures that had already been established.

For now, the promise of human embryonic cells rests largely on studies of their counterparts in mice, creatures that possess the same basic mammalian body plan as people despite a separation of 100 million years of evolution.

Embryonic cells are a sort of magic clay that can be shaped into organs and tissues. Biologists try to drive the cells down particular paths of development by exposing them to the chemical signals and physical stimuli the cells are thought to experience in the developing embryo. With such methods, mouse embryonic cells have been induced to develop into the mature cells typical of 19 different kinds of tissue, including those of heart, skin, brain, bone and pancreas.

Promising Advances

But the promise of embryonic stem cells for medicine rests on more than their powers to morph into any body tissue. In the lab, they exhibit another amazing property the ability to assemble spontaneously into structures seen in living tissues. Researchers do not understand the organizing process and do little to make it happen; the cells are just engineered to self-assemble, given the right cues and conditions.

Last year Dr. Shin-Ichi Nishikawa and colleagues at Kyoto University in Japan reported that they had coaxed mouse embryonic stem cells to build themselves into blood vessels. The Kyoto biologists grew the cells on a dish lined with collagen, the fiber that gives the skin its stretchiness; the collagen may have alerted the cells that they were in a place where blood vessels were needed.

In their dish, the precursor cells developed after several days into both the soft muscle cells that make up the wall of blood vessels and the special lining cells that coat the walls. And the wall cells and lining cells then spontaneously assembled into tubes like those of blood vessels.

Last April, in an even more striking piece of alchemy, scientists at the National Institutes of Health, including Dr. Nadya Lumelsky and Dr. Ronald D. G. McKay, described a five-step method for making mouse embryonic cells assemble into hormone-producing clusters like the islets of the pancreas gland.

The islets are the source of insulin, the hormone that alerts cells to take up glucose from the blood, and they also generate three lesser-known hormones called glucagon, somatostatin and pancreatic polypeptide, each produced by a different type of cell. The N.I.H. team found that their pancreas-directed embryonic cells morphed into the four different kinds of pancreatic cells, assembled themselves in the laboratory dish into structures resembling islets, and even churned out insulin when exposed to glucose just as real pancreatic islets do.

The researchers then injected some of these artificially made islets into diabetic mice. They continued making insulin, though not enough to cure the mice of diabetes. Still, the experiment underlined the cells' potential for patching up the body.

Human embryonic cells can in principle provide an inexhaustible source of islets, and of many other critical tissues that are damaged in disease. Embryonic stem cells possess and can gain access to the entire manual of genetic instructions for generating and regenerating the body. Given the bare minimum of appropriate cues, it seems, they will mold themselves into the components of the right tissue.

Human embryonic cells are expected to behave in the same general way as mouse cells, although few studies of them have been done. In August, University of Wisconsin researchers reported that human embryonic cells could be converted into blood- forming cells. The finding may prove important to blood banks because in principle it offers a way of growing an inexhaustible supply of red blood cells and platelets free of infectious agents.

Researchers in Israel have converted human embryonic cells into heart muscle, and other groups are working out ways to drive the cells down paths of development that lead to brain and pancreas tissue.

High Hurdles

But research on embryonic stem cells is at an embryonic stage, with many hurdles yet to be overcome before they reach the clinic. Injected into mice, the unchanged cells form not an embryo but a grisly tumor full of hair and teeth and known as a "monster cancer" or teratoma.

Another obvious problem is that embryonic cells drawn from some tissue bank may not exactly match a patient's immune system. But embryonic cells seem less antagonistic to the immune system than are ordinary cells. And there may be clever ways of getting around the immune incompatibility issue.

One idea is to repress the genes that make embryonic cells appear foreign to their host. Another is a co-transplant, that of first inserting blood-making cells into a patient's bone marrow and then heart-repairing cells made from the same embryonic line. The blood-making cells can induce immunological tolerance of their presence, preventing the patient's immune system from attacking any other cells derived from the same embryo.

Adult Stem Cells

Embryonic stem cells are of great interest because of their all-purpose nature. But the body's adult stem cells also hold high medical promise. Adult stem cells, if they could be extracted from each patient as need arose, could be used without any risk of immune rejection.

Most adult stem cells are specialized to repair just the tissue they are found in. Skin stem cells repair the skin. Hematopoietic stem cells generate all the cells of the blood and immune system. Intestinal stem cells provide a new lining for the gut. So far some 13 types of adult stem cell have been identified, according to the National Institutes of Health.

Years of effort have failed to bring to light the heart's stem cells, reinforcing the idea that the heart muscle cells are never renewed in lifetime. But this dogma came under challenge this year when a flurry of reports suggested that the heart was the wrong place to look for them. The cells, according to the challengers, reside in the bone marrow.

Dr. Donald Orlic of the National Institutes of Health, and Dr. Piero Anversa of New York Medical College in Valhalla, have found that bone marrow cells injected into the hearts of mice given heart attacks will develop into both heart muscle cells and the cells that build blood vessels. The two types of cells integrated into the stricken heart and improved its function.

This year they reported taking their research a step further toward an elegant, minimalist heart attack therapy. They injected animals with two signaling proteins, known as cytokines, that are known to make bone marrow stem cells proliferate and rush out into the bloodstream. They then induced heart attacks in the mice by tying off a blood vessel to the heart.

The activated stem cells homed in on the damaged heart tissue and grew into new heart muscle, enabling most of the animals to survive the heart attack.

The researchers are now testing how effective the treatment is when the cytokines that mobilize the stem cells from the bone marrow are injected after a mouse heart attack, not before. If the stricken mice still benefit, "that could have tremendous clinical importance," Dr. Orlic said.

Cells from the bone marrow can also turn into liver cells but do so rather inefficiently. "The natural propensity for hematopoietic stem cells to repair the liver is poor," said Dr. Markus Grompe, a liver expert at the Oregon Health and Science University.

The concept of using cytokines to stimulate adult stem cell production is already in use in bone marrow transplants. Surgeons used to transplant the whole marrow because they could not identify the 1 in every 100,000 marrow cells that is a true stem cell. Now, instead of a bone puncture, the donor is injected with a cytokine that makes the stem cells proliferate and enter the bloodstream, where they can be captured by virtue of characteristic marker proteins they carry on their surface.

Adult stem cells not only repair the body but conduct vigorous daily regeneration of its most abraded tissues. A single human skin stem cell grown in a laboratory dish can generate enough cells to clothe the entire body in skin.

The hematopoietic stem cells produce billions of new progeny every day to replace both the white blood cells, which die fighting pathogenic invaders, and the red blood cells, which last only two months before wearing out. Even the brain has stem cells, which are estimated to generate one new neuron per 2,000 every day, according to Dr. Fred H. Gage of the Salk Institute. New neurons are used in the brain regions dedicated to place and face recognition, to the sense of smell and maybe to other modules.

Clever Stem Cell Tricks

A salient property of stem cells is one that biologists call asymmetric division. The body's mature cells do not divide very much, but when they do, a mother cell produces two identical daughter cells. A stem cell, on the other hand, can divide to produce one stem cell and one progenitor or transit cell, which then proliferates into the tissue's mature, fully formed cells. Because each stem cell regenerates itself on division, the number of stem cells stays constant.

A stem cell can also divide into two stem cells, as embryonic cells do when kept in lab culture. Mature cells kept in culture will divide only about 50 times and then lapse into senescence because of a division-counting mechanism on their chromosomes that limits their ability to proliferate.

Embryonic cells have the power to override the division-counting system and will grow and divide indefinitely. They are in this sense immortal. A single culture of embryonic stem cells can in principle produce enough cells for everyone. Adult stem cells, by contrast, proliferate rather poorly in culture.

Embryonic cells may provide the ideal vehicle for gene therapy, the idea of introducing genes to correct harmful genetic defects. Gene therapists have long tried to insert curative human genes into a patient's cells on the back of harmless viruses. But the virus delivery method has proved inefficient, and it still lingers under the cloud caused by the death of a patient at the University of Pennsylvania in 1999.

Cells in culture can be manipulated much more easily than those in the body. The physician can select just the cells in which a gene has integrated correctly, grow them up and insert them into the patient. Researchers have routinely generated new strains of mice by manipulating mouse embryonic cells, and some aspects of this technology may prove useful for improving human embryonic cells.

As the power and abilities of stem cells become apparent, biologists have become increasingly optimistic about the chances for treating otherwise intractable diseases.

"A multitude of therapeutic uses can be envisioned," Dr. Elaine Fuchs and Dr. Julia Segre of the University of Chicago wrote recently in the journal Cell. They cited hope for the treatment of Alzheimer's, spinal cord injuries, Parkinson's, heart disease, diabetes and baldness.

Though the body is made up almost entirely of mature cells, its continued existence depends on a handful of stem cells. The body's hierarchy of cells resembles that of the pieces in a chess set. Like the queen, the all-purpose cells of the embryo can perform all permissible moves. The adult stem cells, as diminished in power as bishops, knights and rooks, can make only a subset of the queen's moves. The mature cells are mere pawns, with a single role.

The role of king is played by a special cluster of embryonic cells known as the embryonic germ cells. The germ cells are set aside at an early stage and protected from the maturing process that affects all the other embryonic cells. Migrating to the tissues that will become ovary or testis, the germ cells' role is to produce eggs or sperm. But if grown in a laboratory dish, the germ cells display the ability of the embryonic cells to generate all the tissues of the body.

Just as chess depends on the fate of the king, the germ cells are central to the game of life. Under evolution's rules, the body is just a disposable and temporary container designed to allow the germ cells to get their genes into the next generation. The promise of stem cell research is that it may allow doctors to bend the rules of this harsh game just a little, by using the vast generative power of stem cells to extend life and health.

Copyright 2001 The New York Times Company