TIME: Almanac 1993/TIME Almanac 1993.iso/time/093091/0930350.000

Text File | 1992-08-28 | 26.9 KB | 562 lines

                                                                                MEDICINE, Page 56

COVER STORIES

Making Babies


More than a million couples seek treatment for infertility each
year. Now some remarkable insights into the mating dance of sperm
and egg are bringing answers to their prayers.

By PHILIP ELMER-DEWITT -- Reported by Ann Blackman/Washington,
Barbara Dolan/Norfolk and Jeanne McDowell/Los Angeles


    Couched in a halo of nutrient cells, an egg smaller than
the dot on an i drifts slowly down a Fallopian tube, one of a
pair of narrow passages that lead from a woman's ovaries to her
womb. Like a beacon guiding ships at night, the egg sends forth
a calling signal. A convoy of sperm -- the remnants of an
armada that was once a couple of hundred million strong -- sails
into view, their long tails thrashing vigorously. Lured by the
chemical signal, several hundred of the most energetic swimmers
close in on the egg, their narrow tips unleashing a carefully
timed sequence of biochemical salvos. One substance dissolves
the jelly-like veil surrounding the egg. Another softens the
egg's tough outer shell, preparing it for penetration. In the
last moments before conception, a few dozen sperm race to break
through the final barricade.

    One and only one succeeds. The instant it tunnels its way
past the egg's outer layer, an electric charge fires across the
membrane and a signal from the sperm causes the eggshell to snap
shut, blocking entry to any remaining contenders. The successful
seed then releases its tightly coiled package of DNA, which
fuses with the egg's own DNA and sets in motion a series of
genetic events that culminate, nine months later, in the birth
of a new human being.

    That is how it is supposed to work. And for hundreds of
thousands of years, without anyone knowing quite how or why, it
has worked -- well enough to perpetuate the species, populate
the planet and bring the joy and responsibility of children to
countless generations of parents.

    But what if it doesn't work? What if egg meets sperm and
nothing happens? Human sexual reproduction, as couples even
before Sarah and Abraham have known, can be a heartbreakingly
unreliable process. Even under the best of circumstances -- a
fertile couple having intercourse at the optimum moment in the
woman's cycle -- it fails 3 times out of 4. When conditions are
less than ideal -- when the woman is over 35, for example, or
the man's sperm is defective or in short supply -- the odds
lengthen dramatically.


    America today is in the midst of an infertility epidemic,
the unforeseen consequence of a variety of historical and
socioeconomic trends. The advent of the Pill, the women's
movement and an economy that pushes women into the workplace
during their most fertile years have led many members of the
baby-boom generation to wait so long to have children that they
are in danger of waiting forever. This same generation was also
party to the sexual revolution, and that too has taken a toll.
With exposure to more sex partners came a sharp rise in sexually
transmitted diseases and other infections that can impair
fertility. In addition, tens of thousands of women now in their
30s and 40s were born with malformed reproductive systems as a
result of their mothers' use of the drug DES
(diethylstilbestrol), which was widely prescribed in the 1940s
and '50s to prevent miscarriage.

    Taken together, more than 1 in 12 U.S. couples has
difficulty conceiving -- a number that is as high as 1 in 7 for
couples in the thirtysomething years. And given the size of that
age group, there have never been as many people looking for
help. The number of doctor visits for fertility problems nearly
tripled between 1968 and 1984. Last year more than a million new
patients sought treatment, six times as many people as were
treated for lung cancer and 10 times the number of reported
cases of AIDS.

    The sad fact is that half the people who seek assistance
never overcome their infertility. But there is real hope for
even the most difficult cases. Through a series of remarkable
advances, scientists have opened a new window on the mysteries
of fertilization that shows for the first time not only how the
process works but also what can be done when it doesn't. Doctors
today can manipulate virtually every aspect of the reproductive
cycle, from artificially ripening eggs in the ovary to inserting
individual sperm directly into the egg's inner membrane. Now
researchers at several U.S. clinics are pushing the scientific
envelope even further, screening embryos for genetic defects in
the lab before placing them in their mothers' wombs.

    The result is a reproductive revolution: an explosion of
new techniques for overcoming infertility and an unprecedented
rush by would-be parents to take advantage of them. Thirteen
years after the birth of the first test-tube baby, Louise Brown,
in England, in vitro fertilization (IVF) has not only reset the
biological clock for thousands of patients -- and produced some
10,000 babies in the U.S. alone -- but spawned a host of new
procedures, like GIFT, ZIFT, microinjection and zona drilling,
that offer even greater promise. Today, using the new
technology, an infertile couple in their mid-30s has as good a
chance of getting pregnant artificially as a pair of fertile
teenagers having unprotected sex at any random moment the
old-fashioned way.

    Families can be pieced together with borrowed sperm,
borrowed eggs and borrowed wombs. Women are having babies long
after their prime childbearing year -- even after menopause. In
yet another twist, Arlette Schweitzer, 42, of Aberdeen, S.
Dak., is expected to give birth to her own twin grandchildren
next month, having served as a surrogate for her daughter
Christa, who was born without a uterus. "Next to Christa, I'm
the happiest woman in the world," says Schweitzer. "We feel so
blessed."


    The brave new technologies stir up conflicting feelings,
breeding hope and despair where once there was resignation. The
high price of in vitro treatments (ranging from $6,000 to more
than $50,000 per live birth) means that only the rich and
well-insured can afford them. Patients who have undergone round
after round say it is like riding an emotional roller coaster;
you never know when you are going to run into a brick wall and
have your heart broken.

    The new techniques have also given birth to once
unimaginable ethical dilemmas. Do sperm and egg donors have a
claim on their biological offspring, and vice versa? Do embryos,
frozen or thawed, have a constitutional right to life? How much
manipulation of genetic material will society be willing to
permit? "Technology makes us look at our most cherished
conceptions of who we are and what we want to be," says Dr.
Kenneth Ryan, a professor of reproductive biology at Harvard
Medical School. "People have to decide what kind of society they
want to live in."

    But all these issues pale before the newly revealed
miracle of fertilization, an event so dizzyingly complex that
researchers say the more they know, the more they wonder that
it works as often as it does. The actual merger of egg and sperm
turns out to be one of the most straightforward steps in the
process -- and the easiest to duplicate in a test tube. The
events that occur before and after that union, scientists say,
are where the real troubles lie.

    The long road to conception actually begins seven months
before a woman is born, when microscopic eggs start to form in
the buds that will become her ovaries. Unlike the testicles of
a man, which continuously churn out sperm at the prodigious
rate of 1,000 per sec. (30 billion a year), the ovaries never
produce any new eggs. The eggs a woman is born with -- usually
about 2 million -- are all she will ever have. By puberty,
normal degeneration will have reduced that number to about
400,000. When the woman exhausts the supply, her ovaries will
virtually shut down, an event she experiences as menopause.

    The limited supply of eggs is believed to be a chief
reason that fertility decreases with age. Each month, starting
at puberty, hundreds of eggs begin the maturation process. One
of them, growing in a fluid-filled sac called the follicle,
quickly establishes itself as the first among equals. In a
normal cycle, only that single egg will be released to the
Fallopian tubes for possible fertilization. About 1,000 more
will wither away and disappear. So although a woman may have
400,000 eggs to start with, the number she can effectively use
is closer to 400.

    To make matters worse for the aging female, the eggs that
remain in her ovaries get older and less fertile with each
passing year. Recent studies of egg donation provide strong
evidence that it is the age of the eggs, and not the age of the
reproductive system, that causes fertility to decline sharply
after age 40: older women who receive eggs from younger women
get pregnant at rates comparable to the age of the egg donor,
not the age of the recipient.

    None of this is to say that men do not play a role in
infertility. On the contrary, the sperm of the human male is
notoriously prone to defects. A typical sample is riddled with
"pinheaded" sperm, which lack a full complement of DNA,
two-headed freaks, and sperm that cannot swim a straight line.
Urologists estimate that when a couple experiences infertility,
so-called male factors are just as likely to be responsible as
female ones. But because of the way sperm are manufactured,
assembly-line fashion in the factory of the testes, not much can
be done to change either their quality or rate of production
(although scientists have developed some extraordinary new
procedures to help deficient sperm accomplish their mission).
Even the varicocelectomy, a widely prescribed operation that
enhances sperm production by removing a varicose vein in the
scrotum, seems from recent studies to have little effect on a
couple's ability to conceive.

    The sequence of events by which eggs mature and ovulate,
by contrast, lends itself to all kinds of tinkering. Every step
in that process is controlled by hormones, and much of the
infertility work done in the '60s and '70s involved finding
which hormones were out of balance and how to adjust them. A
woman whose ovaries do not release their eggs properly, for
example, might be given human chorionic gonadotropin, which
triggers ovulation. A woman who tends to miscarry may be given
progesterone, which helps soften the uterine lining to make it
more receptive.

    A widely used drug called Pergonal (menotropin), which for
years was derived from the urine of postmenopausal Italian nuns,
is rich in the hormone that stimulates eggs to develop and form
follicles. This follicle-stimulating hormone usually allows only
one egg to reach full maturity, but when administered in huge
doses it can trick the ovaries into producing more than a dozen
mature eggs in a single cycle. This abundance of eggs is key to
most assisted-reproduction techniques. By fertilizing large
numbers of eggs and selecting the healthiest embryos, fertility
specialists maximize the odds of achieving a successful
pregnancy.

    Hormone treatments can cover a multiple of symptoms. But
there are any number of problems that don't respond to hormone
therapy. A woman's Fallopian tubes may be blocked or rendered
inoperative by scarring from pelvic infections, sexually
transmitted diseases or bits of tissue leaking out of the
uterus, a condition called endometriosis. A man may have too few
sperm that can make the long journey, or his sperm may lack
specific enzymes needed to clear the passage to the egg. Some
couples learn late in the game that they are incompatible at a
cellular level. A woman can be allergic to her husband's sperm;
her antibodies may destroy her partner's seeds before they get
a chance to be sown.

    There are treatments for each of these conditions. Blocked
Fallopian tubes can be freed or cleared of obstructions by a
variety of operations, ranging from laser-beam surgery to
inflating a tiny balloon within the clogged passage. Men with
extremely low sperm counts can be helped toward fatherhood by
artificial insemination, which puts what sperm they have
directly into the cervix, or by microinjection, which puts a
single sperm right into the egg. And for couples with
sperm-allergy problems, a procedure known as sperm washing
strips the sperm of some of the chemical antigens that trigger
the allergic reaction.

    But most of these treatments have been supplanted by the
family of techniques known as in vitro fertilization. The beauty
and power of IVF are that it allows doctors to take many key
events in reproduction out of the body, where they are subject
to the vagaries of human biology, and perform them in vitro, "in
glass." By removing mature eggs from the ovaries, mixing them
with sperm in a Petri dish and reintroducing the resulting
embryos directly into the uterus, doctors can bypass most of the
important barriers to fertility, from low sperm counts to
nonfunctioning Fallopian tubes.

    The status of IVF has undergone a striking transformation
in the past decade. It used to be considered an option of last
resort; with success rates running below 5%, most doctors put
couples through the full gamut of conventional therapies before
turning to IVF. Today a couple in their 30s with undiagnosed
infertility is likely to be told to skip invasive tests and
exploratory surgeries and go straight to in vitro or related
technologies. Streamlined procedures and lowered costs are part
of the reason. But it was the development of two variations on
the basic IVF procedure -- GIFT and ZIFT -- and the impressive
success rates they have produced that have made believers of
most doctors.

    The major sticking point of the original procedure, it
turned out, was that the embryos just wouldn't stick. Helped by
hormone treatments, a woman might produce dozens of eggs each
cycle. Her husband's sperm might fertilize 10 of them. But for
reasons that remained mysterious, the embryos simply refused to
take root -- or implant -- on the walls of the uterus. Even the
best-run clinics were getting success rates not much higher than
15% to 20% just five years ago.

    Scientists now know that implantation is one of the most
difficult hurdles in the human reproductive system. It is
estimated that even among perfectly fertile couples, as many as
one-third of all pregnancies are lost, before anyone knows they
have begun, because the embryos fail to implant in the uterus
wall. Only in the past few years have researchers begun to
understand why this is so.

    A key breakthrough came in the mid-1980s at Dr. Ricardo
Asch's laboratory at the University of Texas at San Antonio.
Asch was trying to find a simpler way to do IVF, one that would
not require the skills of an embryologist, when he hit upon the
procedure he called gamete intra-Fallopian transfer, or GIFT.
Rather than attempting fertilization in a Petri dish, he simply
loaded the sperm and eggs (known to biologists as gametes) into
a fine pipette and inserted them into the Fallopian tube, where
he hoped they would take care of business by themselves. Not
only did they fertilize, but they implanted as well -- at a
much higher rate than he expected.

    Scientists attribute the implantation rates of GIFT to the
way in which the fertilized embryo enters the uterus. In IVF
the embryo is squirted, rather violently, into a reproductive
tract that has been pretty roughly treated, first by various
hormone treatments, then by the egg-retrieval procedure. In
GIFT, by contrast, the embryo drifts quietly into the uterus,
much as it would naturally. To further improve the success
rates, Asch's researchers tried fertilizing the egg in a lab
dish and then placing the pre-embryo, or zygote, directly into
the Fallopian tube -- a procedure known as ZIFT (zygote
intra-Fallopian transfer).

    The results were startling. Using GIFT and ZIFT, clinics
were soon reporting implantation rates two to three times as
high as those achieved in their own IVF facilities. Among
couples for whom sperm quality is not a factor, a single cycle
of GIFT or ZIFT at Asch's clinic can result in pregnancy 40% to
50% of the time. A healthy, fertile couple trying to conceive
naturally in any given month has about a 25% success rate.

    The latest clue in the mystery of implantation was hit
upon by scientists working on a completely different problem:
lazy sperm. Some sperm lack the ability to penetrate the egg's
outer membrane, or zona pellucida, often as a result of old
testicular injuries or early exposure to toxic chemicals.
Several methods have been devised to give these sperm a boost,
including microinjection (the sperm is inserted directly into
the egg by means of a microscopic needle) and partial zona
drilling (a tiny hole is made in the egg's protective shell).

    It was while working with patients with severe sperm
deficiencies that researchers noticed something surprising. Eggs
whose shells had been poked open were doing a much better job
of sticking to the uterus wall. In a trial performed by Dr.
Jacques Cohen, one of the scientists who developed the PZD
procedure, embryos successfully lodged in the womb at a rate
more than five times the national average for IVF. "I was so
excited I couldn't sleep at night," says Cohen. Apparently eggs
with a hole in their outer membrane somehow benefit from that
hole. Cohen theorizes that embryos that don't implant may be
having trouble "hatching" through the shell that housed the
original egg. The tiny hole Cohen makes to help the sperm get
in may be helping the embryo get out -- and may suggest a method
for helping increase implantation rates across the board.

    In April scientists from Israel and the U.S. reported a
new finding that may offer yet another way to help infertile
couples. It had long been assumed that there was no
communication between egg and sperm until they collided in the
Fallopian tube. But by closely watching the behavior of sperm
in test tubes containing the fluid from an egg's follicular sac,
an interesting effect was observed. A small number of sperm
seemed to change their swimming patterns in response to
chemicals secreted by the egg or cells around the egg.

    It was not a dramatic effect, and not all eggs emitted
even this weak chemical signal. But when the researchers
correlated the results, they discovered a startling pattern:
only eggs that emitted the "come hither" message were
successfully fertilized. "This indicated to us that attraction
may indeed be a key process in fertilization," says Michael
Eisenbach at Israel's Weizmann Institute of Science. Now
Eisenbach is trying to find out whether this phenomenon could
be exploited to help treat the most stubborn infertility cases.

    Scientists in South Korea are on the verge of a
breakthrough in a procedure doctors have been dreaming about for
some time: the freezing and storage of unfertilized eggs. Sperm
and embryos are regularly frozen for later use, but not eggs,
which quickly lose their viability when manipulated outside the
body. But Dr. Kwang Yul Cha, an endocrinologist at Cha Women's
Hospital in Seoul, reports that his team has produced two
pregnancies from eggs matured not in an ovary but in a Petri
dish -- a major step in the eventual perfection of egg freezing.
Many scientists expect that the procedure will be available
within the next few years.

    That could be a godsend for a young woman facing surgery
or chemotherapy that would destroy the functioning of her
ovaries. Such a woman would have the option of putting her
healthy eggs on ice for future use. That option might also
appeal to, say, a professional woman inclined to postpone
childbearing. Theoretically, at least, she could store her best,
grade-A eggs during her most fertile years and pull them out of
the deep freezer at a later age should she run into trouble
conceiving. Not everyone, though, would approve this use of an
expensive technology.

    Even more provocative is a new area of research that
combines the techniques of in vitro fertilization with the
latest advances in genetic screening. Abnormalities like
sickle-cell anemia or cystic fibrosis are present in the genetic
code from the moment of conception. Since embryos in their
earliest stages are fairly forgiving -- they can lose a cell or
two without impairing their subsequent development -- it is
theoretically possible to remove a cell from, say, a 16-cell
embryo, test it for a suspected defect, and get the answer
before that embryo is inserted into the uterus for implantation.

    Embryologists at several U.S. labs are doing just that.
Doctors at Chicago's Illinois Masonic Medical Center have
screened embryos from 15 couples who have a known risk of
carrying such diseases as Tay-Sachs, a rare, crippling condition
that often results in death by age four. Last week doctors at
Cornell Medical Center began clinical studies on embryos at risk
for cystic fibrosis.


    These experiments are sure to arouse protests. Today most
in vitro clinics are very careful never to purposely destroy
viable embryos. Even when couples agree to freeze embryos, they
are required to sign an agreement specifying what will happen
to any embryos they don't need: they can be donated to couples
that can't produce their own or donated to research. But the
premise of pre-embryotic genetic testing is that defective
embryos will be destroyed. If the problem is a debilitating
disease like Tay-Sachs, this may be justifiable. But what if
couples choose to reject embryos whose only offense is that they
are of the wrong sex? "You're dealing with human tissues from
a human body," says Lynne Lawrence, at the American Fertility
Society. "Like sex, it tends to cut near and dear to people's
hearts and raises a red flag."

    Society has just begun to wrestle with the financial
burden of assisted reproduction. "It takes courage and cash,"
says Dr. Georgeanna Jones, whose work with her husband, Dr.
Howard Jones, in Norfolk, Va., produced the first IVF baby in
the U.S. A single in vitro cycle can cost $6,000 to $8,000, a
burden most medical plans are not eager to share. Nine states
have passed laws requiring insurance companies to cover the
cost of infertility treatments, but resistance in the remaining
states is strong. The question, says Leroy Walters, at
Georgetown University's Kennedy Institute of Ethics, is "to what
extent society has a responsibility to assist couples that are
infertile." In Walters' opinion, society should pay for the
diagnosis of the problem, "but beyond that, given the cost, I'd
place the financial responsibility on the couples themselves."
It may, for instance, be more in society's interest to encourage
intractably infertile couples to adopt.

    The Federal Government has tried to steer clear of
infertility issues. Under pressure from right-to-life lobbies,
it quietly cut funds for in vitro research in 1980, despite a
Health Department study that called such a ban "neither
justifiable nor wise." Last fall Congress appropriated $3
million for three contraceptive centers and five infertility
centers. But because of the government's ban on funding IVF
research, the scientists haven't been able to begin their work.
"Britain and Australia are surpassing us in research because of
the restraints we face in this country," says Harvard's Ryan.
"The U.S. government has created a moral vacuum."

    And where there is a moral vacuum, there are lawsuits.
Around the country, a number of bizarre court cases have cropped
up as a result of ambiguities in the rules governing the new
technologies. In one peculiar case, a wealthy couple died in a
plane accident, leaving two frozen embryos as their only direct
heirs; a court decided that the embryos could not inherit the
estate. In a case that is still pending, a divorced Tennessee
couple are battling over whether the woman has the right to make
use of frozen embryos created while the couple were still
married.


    Making matters more confusing for consumers is the fact
that success rates among the nation's 225 IVF centers vary
wildly -- from zero for new ones to 40% and better at some of
the top clinics. And infertility specialists are not always what
they claim to be. Some obstetricians print INFERTILITY on their
business cards on the strength of three-month residency training
programs. "They pick up infertility because it's easier than
delivering babies at 3 a.m.," scoffs Dr. Richard Marrs, who
headed the ethics committee of the American Fertility Society.

    Horror stories abound. It is not unusual for a poorly
trained physician to schedule advanced infertility treatments
-- even surgery -- on a woman without first checking her
partner's sperm count. A lawsuit is pending against a physician
in Torrance, Calif., who is accused of duping patients into
believing he was performing in vitro fertilization when he
wasn't even collecting eggs. Consumers are advised to seek
guidance from either the American Fertility Society, based in
Birmingham, or Resolve, a national infertility organization with
headquarters in Somerville, Mass. "You need to be a careful
consumer," warns Dr. Arthur Wisot, a Redondo Beach, Calif.,
infertility specialist. "If you're going to invest all your
life's hopes and dreams, you should at least check out the
qualifications of the medical group."

    Pamela and Jonathan Loew know about investing all their
hopes and dreams in achieving pregnancy. The Los Angeles couple
went through a five-year effort that included hormone
treatment, artificial insemination, an ectopic pregnancy, sperm
washing and finally GIFT. "Intellectually you know it's a
medical problem," says Pamela, "but emotionally you can't get
it out of your mind that you're not like a normal woman."

    When Pamela and Jonathan learned during a Las Vegas
vacation that their first GIFT procedure had failed, they sat
together in a rental car and cried. "It was pretty devastating,"
recalls Pam. When Jonathan got a call telling him that their
second GIFT attempt was successful and that his wife was at long
last pregnant, he was incredulous: "I couldn't believe that
after five years we had finally hit the jackpot."

    Today the passage of time has dulled the pain. Little
Alexandra is 17 months old, and her parents are thinking about
having a second child. They still have 12 frozen embryos saved
from their second GIFT procedure, and during the next few
months those embryos will be thawed and inserted, a few at a
time. But whether it works or not is of much less moment to
Pamela and Jonathan now than it would have been two years
earlier. As baby Alex sits in the living room, engrossed in a
music video playing on the VCR, they know full well that they
are already ahead of the game.