http://www.nytimes.com/2001/12/18/health/genetics/18NEXT.html?pagewanted=print
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
By NICHOLAS WADE