| Time
Magazine - Nov. 3, 2002 |
By J. MADELEINE NASH
|
Original article: http://www.time.com/time/health/article/0,8599,386873,00.html
As the crystal probe slides across her belly, Hilda Manzo,
33, stares wide-eyed at the video monitor mounted on the
wall. She can make out a head with a mouth and two eyes.
She can see pairs of arms and legs that end in tiny hands
and feet. She can see the curve of a backbone, the bridge
of a nose. And best of all, she can see movement. The
mouth of her child-to-be yawns. Its feet kick. Its hands
wave.
Dr. Jacques Abramowicz, director of the University of
Chicago's ultrasound unit, turns up the audio so Manzo
can hear the gush of blood through the umbilical cord
and the fast thump, thump, thump of a miniature heart.
"Oh, my!" she exclaims as he adjusts the sonic scanner
to peer under her fetus' skin. "The heart is on the left
side, as it should be," he says, "and it has four chambers.
Look - one, two, three, four!"
Such images of life stirring in the womb - in this case,
of a 17-week-old fetus no bigger than a newborn kitten - are
at the forefront of a biomedical revolution that is rapidly
transforming the way we think about the prenatal world.
For although it takes nine months to make a baby, we now
know that the most important developmental steps - including
laying the foundation for such major organs as the heart,
lungs and brain - occur before the end of the first three.
We also know that long before a child is born its genes
engage the environment of the womb in an elaborate conversation,
a two-way
dialogue that involves not only the air its mother breathes
and the water she drinks but also what drugs she takes,
what diseases she contracts and what hardships she suffers.
One reason we know this is a series of remarkable advances
in mris, sonograms and other imaging technologies that
allow us to peer into the developmental process at virtually
every stage - from the fusion of sperm and egg to the
emergence, some 40 weeks later, of a miniature human being.
The extraordinary pictures on these pages come from a
new book that captures some of the color and excitement
of this research: From
Conception to Birth: A Life Unfolds (Doubleday), by photographer Alexander Tsiaras and writer Barry Werth.
Their computer-enhanced images are reminiscent of the
remarkable fetal portraits taken by medical photographer
Lennart Nilsson, which appeared in Life magazine in 1965.
Like Nilsson's work, these images will probably spark
controversy. Antiabortion (read: pro-life – RJ)
activists may interpret them as evidence that a fetus
is a viable human being earlier than generally believed,
while pro-choice (read: pro-abortion – RJ)
advocates
may argue that the new technology allows doctors to detect
serious fetal defects at a stage when abortion is a reasonable
option.
The other reason we know so much about what goes on inside
the womb is the remarkable progress researchers have made
in teasing apart the sequence of chemical signals and
switches that drive fetal development. Scientists can
now describe at the level of individual genes and molecules
many of the steps involved in building a human, from the
establishment of a head-to-tail growth axis and the budding
of limbs to the sculpting of a four-chambered heart and
the weaving together of trillions of neural connections.
Scientists are beginning to unroll the genetic blueprint
of life and identify the precise molecular tools required
for assembly. Human development no longer seems impossibly
complex, says Stanford University biologist Matthew Scott.
"It just seems marvelous."
How is it, we are invited to wonder, that a fertilized
egg - a mere speck of protoplasm and dna encased in a
spherical shell - can generate such complexity? The answers,
while elusive and incomplete, are beginning to come into
focus.
Only 20 years ago, most developmental biologists thought
that different organisms grew according to different sets
of rules, so that understanding how a fly or a worm develops
- or even a vertebrate like a chicken or a fish - would
do little to illuminate the process in humans. Then, in
the 1980s, researchers found remarkable similarities in
the molecular tool kit used by organisms that span the
breadth of the animal kingdom, and those
similarities have proved serendipitous beyond imagining.
No matter what the species, nature uses virtually the
same nails and screws, the same hammers and power tools
to put an embryo together.
Among the by-products of the torrent of information pouring
out of the laboratory are new prospects for treating a
broad range of late-in-life diseases. Just last month,
for example, three biologists won the Nobel Prize for
Medicine for their work on the nematode Caenorhabditis
elegans, which has a few more than 1,000 cells, compared
with a human's 50 trillion. The three winners helped establish
that a fundamental mechanism that C. elegans embryos employ
to get rid of redundant or abnormal cells also exists
in
humans and may play a role in aids, heart disease and
cancer. Even more exciting, if considerably more controversial,
is the understanding that embryonic cells harbor untapped
therapeutic potential. These cells, of course, are stem
cells, and they are the progenitors of more specialized
cells that make up organs and tissues. By harnessing their
generative powers, medical researchers believe, it may
one day be possible to repair the damage wrought by injury
and disease. (That prospect suffered a political setback
last week when a federal advisory committee recommended
that embryos be considered the same as human subjects
in clinical trials.)
To be sure, the marvel of an embryo transcends the collection
of genes and cells that compose it. For unlike strands
of dna floating in a test tube or stem cells dividing
in a Petri dish, an embryo is capable of building not
just a protein or a patch of tissue but a living entity
in which every cell functions as an integrated part of
the whole. "Imagine yourself as the world's tallest skyscraper,
built in nine months and germinating from a single brick,"
suggest Tsiaras and Werth in the opening of their book.
"As that brick divides, it gives rise to every other type
of material needed to construct and operate the finished
tower - a million tons of steel, concrete, mortar, insulation,
tile, wood, granite, solvents, carpet, cable, pipe and
glass as well as all furniture, phone systems, heating
and cooling units, plumbing, electrical wiring, artwork
and computer networks, including
software."
Given the number
of steps in the process, it will perhaps forever seem
miraculous that life ever comes into being without a major
hitch. "Whenever you look from one embryo to another,"
observes Columbia University developmental neurobiologist
Thomas Jessell, "what strikes you is the fidelity of the
process."
Sometimes, though, that fidelity is compromised, and the
reasons why this happens are coming under intense scrutiny.
In laboratory organisms, birth defects occur for purely
genetic reasons when scientists purposely mutate or knock
out specific sequences of dna to establish their function.
But when development goes off track in real life, the
cause can often be traced to a lengthening list of external
factors that disrupt some aspect of the genetic program.
For an embryo does not develop in a vacuum but depends
on the environment that surrounds it. When a human embryo
is deprived of essential nutrients or exposed to a toxin,
such as alcohol, tobacco or crack cocaine, the consequences
can range from readily apparent abnormalities - spina
bifida, fetal alcohol syndrome - to subtler metabolic
defects that may not become apparent until much later.
Ironically, even as society at large continues to worry
almost obsessively about the genetic origins of disease,
the biologists and medical researchers who study development
are mounting an impressive case for the role played by
the prenatal environment. A growing body of evidence suggests
that a number of serious maladies - among them, atherosclerosis,
hypertension and diabetes - trace their origins to detrimental
prenatal conditions. As New York University Medical School's
Dr. Peter Nathanielsz puts it, "What goes on in the womb
before you are born is just as important to who you are
as your genes."
Most adults, not to mention most teenagers, are by now
thoroughly familiar with the mechanics of how the sperm
in a man's semen and the egg in a woman's oviduct connect,
and it is at this point that the story of development
begins. For the sperm and the egg each contain only 23
chromosomes, half the amount of dna needed to make a human.
Only when the sperm and the egg fuse their chromosomes
does the tiny zygote, as a fertilized egg is called, receive
its instructions to grow. And grow it does, replicating
its dna each time it divides - into two cells, then four,
then eight and so on.
If cell division continued in this fashion, then nine
months later the hapless mother would give birth to a
tumorous ball of literally astronomical proportions. But
instead of endlessly dividing, the zygote's cells progressively
take form. The first striking change is apparent four
days after conception, when a 32-cell clump called the
morula (which means "mulberry" in Latin) gives rise to
two distinct layers wrapped around a fluid-filled core.
Now known as a blastocyst, this spherical mass will proceed
to burrow into the wall of the uterus. A short time later,
the outer layer of cells will begin turning into the placenta
and amniotic sac, while the inner layer will become the
embryo.
The formation of the blastocyst signals the start of a
sequence of changes that are as precisely choreographed
as a ballet. At the end of Week One, the inner cell layer
of the blastocyst balloons into two more layers. From
the first layer, known as the endoderm, will come the
cells that line the gastrointestinal tract. From the second,
the ectoderm, will arise the neurons that make up the
brain and spinal cord along with the epithelial
cells that make up the skin. At the end of Week Two, the
ectoderm spins off a thin line of cells known as the primitive
streak, which forms a new cell layer called the mesoderm.
From it will come the cells destined to make the heart,
the lungs and all the other internal organs.
At this point, the
embryo resembles a stack of Lilliputian pancakes - circular,
flat and horizontal. But as the mesoderm forms, it interacts
with cells in the ectoderm to trigger yet another transformation.
Very soon these cells will roll up to become the neural
tube, a rudimentary precursor of the spinal cord and brain.
Already the embryo has a distinct cluster of cells at
each end, one destined to become the mouth and the other
the anus. The embryo, no larger at this point than a grain
of rice, has determined the head-to-tail axis along which
all its body parts will be arrayed.
How on earth does this little, barely animate cluster
of cells "know" what to do? The answer is as simple as
it is startling. A human embryo knows how to lay out its
body axis in the same way that fruit-fly embryos know
and C. elegans embryos and the embryos of myriad other
creatures large and small know. In all cases, scientists
have found, in charge of establishing this axis is a special
set of genes, especially the so-called homeotic homeobox,
or hox, genes.
Hox genes were first discovered in fruit flies in the
early 1980s when scientists noticed that their absence
caused striking mutations. Heads, for example, grew feet
instead of antennae, and thoraxes grew an extra pair of
wings. hox genes have been found in virtually every type
of animal, and while their number varies - fruit flies
have nine, humans have 39 - they are invariably arrayed
along chromosomes in the order along the body in which
they are supposed to turn on.
Many other genes interact with the hox system, including
the aptly named Hedgehog and Tinman genes, without which
fruit flies grow a dense covering of bristles or fail
to make a heart. And scientists are learning in exquisite
detail what each does at various stages of the developmental
process. Thus one of the three Hedgehog genes - Sonic
Hedgehog, named in honor of the cartoon and video-game
character - has been shown to play a role in making at
least half a dozen types of spinal-cord neurons. As it
happens, cells in different places in the neural tube
are exposed to different levels of the protein encoded
by this gene; cells drenched in significant quantities
of protein mature into one type of neuron, and those that
receive the barest sprinkling mature into another. Indeed,
it was by using a particular concentration of Sonic Hedgehog
that neurobiologist Jessell and his research team at Columbia
recently coaxed stem cells from a mouse embryo to mature
into seemingly functional motor neurons.
At the University
of California, San Francisco, a team led by biologist
Didier Stainier is working on genes important in cardiovascular
formation. Removing one of them, called Miles Apart, from
zebra-fish embryos results in a mutant with two nonviable
hearts. Why? In all vertebrate embryos, including humans,
the heart forms as twin buds. In order to function, these
buds must join. The way the Miles Apart gene appears to
work, says Stainier, is by detecting a chemical attractant
that, like the smell of dinner cooking in the kitchen,
entices the pieces to move toward each other.
The crafting of a human from a single fertilized egg is
a vastly complicated affair, and at any step, something
can go wrong. When the heart fails to develop properly,
a baby can be born with a hole in the heart or even missing
valves and chambers. When the neural tube fails to develop
properly, a baby can be born with a brain not fully developed
(anencephaly) or with an incompletely formed spine (spina
bifida). Neural-tube defects, it has been firmly established,
are often due to insufficient levels of the water-soluble
B vitamin folic acid. Reason: folic acid is essential
to a dividing cell's ability to replicate its dna.
Vitamin A, which a developing embryo turns into retinoids,
is another nutrient that is critical to the nervous system.
But watch out, because too much vitamin A can be toxic.
In another newly released book, Before Your Pregnancy (Ballantine Books), nutritionist
Amy Ogle and obstetrician Dr. Lisa Mazzullo caution would-be
mothers to limit foods that are overly rich in vitamin
A, especially liver and food products that contain lots
of it, like foie gras and cod-liver oil. An excess of
vitamin A, they note, can
cause damage to the skull, eyes, brain and spinal cord
of a developing fetus, probably because retinoids directly
interact with dna, affecting the activity of critical
genes.
Folic acid, vitamin A and other nutrients reach developing
embryos and fetuses by crossing the placenta, the remarkable
temporary organ produced by the blastocyst that develops
from the fertilized egg. The outer ring of cells that
compose the placenta are extremely aggressive, behaving
very much like tumor cells as they invade the uterine
wall and tap into the pregnant woman's blood vessels.
In fact, these cells actually go in and replace the maternal
cells that form the lining of the uterine arteries, says
Susan
Fisher, a developmental biologist at the University of
California, San Francisco. They trick the pregnant woman's
immune system into tolerating the embryo's presence rather
than rejecting it like the lump of foreign tissue it is.
In essence, says Fisher, "the placenta is a traffic cop,"
and its main job is to let good things in and keep bad
things out. To this end, the placenta marshals platoons
of natural killer cells to patrol its perimeters and engages
millions of tiny molecular pumps that expel poisons before
they can damage the vulnerable embryo.
Alas, the placenta's defenses are sometimes breached -
by microbes like rubella and cytomegalovirus, by drugs
like thalidomide and alcohol, by heavy metals like lead
and mercury, and by organic pollutants like dioxin and
pcbs. Pathogens and poisons contained in certain foods
are also able to cross the placenta, which may explain
why placental tissues secrete a nausea-inducing hormone
that has been tentatively linked to morning sickness.
One provocative if unproved hypothesis says morning sickness
may
simply be nature's crude way of making sure that potentially
harmful substances do not reach the womb, particularly
during the critical first trimester of development.
Timing is decisive where toxins are concerned. Air pollutants
like carbon monoxide and ozone, for example, have been
linked to heart defects when exposure coincided with the
second month of pregnancy, the window of time during which
the heart forms. Similarly, the nervous system is particularly
vulnerable to damage while neurons are migrating from
the part of the brain where they are made to the area
where they will ultimately reside. "A tiny, tiny exposure
at a key moment when a certain process is beginning to
unfold can have an effect that is not only quantitatively
larger but qualitatively different than it would be on
an adult whose body has finished forming," observes Sandra
Steingraber, an ecologist at Cornell University.
Among the substances Steingraber is most worried about
are environmentally persistent neurotoxins like mercury
and lead (which directly interfere with the migration
of neurons formed during the first trimester) and pcbs
(which, some evidence suggests, block the activity of
thyroid hormone). "Thyroid hormone plays a noble role
in the fetus," says Steingraber. "It actually goes into
the fetal brain and serves as kind of a conductor of the
orchestra."
Pcbs are no longer manufactured in the U.S., but other
chemicals potentially harmful to developing embryos and
fetuses are. Theo Colborn, director of the World Wildlife
Fund's contaminants program, says at least 150 chemicals
pose possible risks for fetal development, and some of
them can interfere with the naturally occurring sex hormones
critical to the development of a fetus. Antiandrogens,
for example, are widely found in fungicides and plastics.
One in particular - dde, a breakdown product of ddt -
has been shown to cause hypospadias in laboratory mice,
a birth defect in which the urethra fails to extend to
the end of the penis. In humans, however, notes Dr. Allen
Wilcox, editor of the journal Epidemiology, the link between
hormone-like chemicals and birth defects remains elusive.
The list of potential threats to embryonic life is long.
It includes not only what the mother eats, drinks or inhales,
explains N.Y.U.'s Nathanielsz, but also the hormones that
surge through her body. Pregnant rats with high blood-
glucose levels (chemically induced by wiping out their
insulin) give birth to female offspring that are unusually
susceptible to developing gestational diabetes. These
daughter rats are able to produce enough insulin to keep
their blood glucose in check, says Nathanielsz, but only
until they become pregnant. At that point, their glucose
level soars, because their pancreases were damaged by
prenatal exposure to their mother's sugar-spiked blood.
The next generation of daughters is, in turn, more susceptible
to gestational diabetes, and the transgenerational chain
goes on.
In similar fashion, atherosclerosis may sometimes develop
because of prenatal exposure to chronically high cholesterol
levels. According to Dr. Wulf Palinski, an endocrinologist
at the University of California at San Diego, there appears
to be a kind of metabolic memory of prenatal life that
is permanently retained. In genetically similar groups
of rabbits and kittens, at least, those born to mothers
on fatty diets were far more likely to develop arterial
plaques than those whose mothers ate lean.
But of all the long-term health threats, maternal undernourishment
- which stunts growth even when babies are born full term
- may top the list. "People who are small at birth have,
for life, fewer kidney cells, and so they are more likely
to go into renal failure when they get sick," observes
Dr. David Barker, director of the environmental epidemiology
unit at England's University of Southampton. The same
is true of insulin-producing cells in the pancreas, so
that low-birth-weight babies stand a higher chance of
developing diabetes later in life because their pancreases
- where insulin is produced - have to work that much harder.
Barker, whose research has linked low birth weight to
heart disease, points out that undernourishment can trigger
lifelong metabolic changes. In adulthood, for example,
obesity may become a problem because food scarcity in
prenatal life causes the body to shift the rate at which
calories are turned into glucose for immediate use or
stored as reservoirs of fat.
But just how does undernourishment reprogram metabolism?
Does it perhaps prevent certain genes from turning on,
or does it turn on those that should stay silent? Scientists
are racing to answer those questions, along with a host
of others. If they succeed, many more infants will find
safe passage through the critical first months of prenatal
development. Indeed, our expanding knowledge about the
interplay between genes and the prenatal environment is
cause for both concern and hope. Concern because maternal
and prenatal health care often ranks last on the political
agenda. Hope because by changing our priorities, we might
be able to reduce the incidence of both birth defects
and serious adult diseases.
With reporting by David Bjerklie and Alice Park/New
York and Dan Cray/Los
Angeles
Copyright © 2002 Time Inc. All rights reserved.
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