Assisted reproductive technology (ART) is going boldly into areas never before explored-and generating social debate along the way.
by Monika Guttman
The baby pictures lining the office walls tout the success stories: dozens and dozens of adorable infants who now fill the hearts and homes of once-childless couples. At holidays and birthdays, hundreds of updates pour in-busy toddlers, grinning preschoolers-sent by grateful former patients who remember the doctor who helped them get pregnant.
For Richard Paulson, M.D., professor of obstetrics and gynecology at the Keck School of Medicine of USC, the snapshots are a reminder of the human factor that is so often lost in the headlines about assisted reproductive technology (ART).
"Reproduction is the essence of life," says Paulson. "The last thing a tree does before it dies is throw its seeds to the wind. It's a strong drive-reflected in the lengths to which people will go to have a child."
Indeed, thanks to rapid developments in the technology and science of cell biology and the demands of couples who no longer view infertility as insurmountable, assisted reproductive technology is going boldly into areas never before explored-and generating much social debate along the way.
Some scientists believe that advances in cell and genomic research might make it possible to develop eggs that have customized genetic material implanted-the genetic blueprint, say, of a woman whose own eggs are too old to be implanted in a donor's viable egg from which the cell nucleus containing the donor's genetic information has been removed.
It is already common for female cancer patients whose treatment will result in the loss of their ovaries to store frozen embryos for implantation after their cancer is in remission. New experiments are suggesting that it may be possible to freeze a small piece of ovary for future egg recovery and fertility, which is similar to the option men have had of storing their sperm for future use.
Most controversial of all is the possibility of cloning humans, growing a complete human organism from a single cell. This technique, which has had occasional, albeit highly unreliable, success in animal experiments, is still considered highly experimental.
"Nearly everyone in the fertility field considers human cloning to be unethical," says Paulson, "and no serious scientist is attempting it. However, the technique of cloning may be useful in other areas of medicine and so-called 'therapeutic cloning' may help infertile couples have their own genetic child, not a clone."
But foremost for Paulson is the human side of the science, the growing numbers of people who turn to technology to help with infertility. About 10 percent of the population of reproductive age-6.1 million men and women-struggle with infertility today, according to the American Society for Reproductive Medicine. Since Louise May Brown, the first test tube baby, was born in 1978, development of new procedures and technologies has given infertile couples more options and more hope. According to RESOLVE, a national infertility association, and other infertility groups, almost half of those who seek infertility treatment today end up with a baby.
Nevertheless, assisted reproductive technology continues to be a controversial medical technique-maybe because it moves an intimate process once confined to the bedroom out into the laboratory and operating room, or maybe because it touches on fundamental views regarding creation and the beginning of life.
"There is no question that early ART attempts were met with many questions-would the new technology be beneficial or whether its use was moral or immoral," notes Paulson. More recently the issue was a woman's reproductive age. Paulson, who performed the procedure that led to a viable pregnancy in a 63-year-old woman who gave birth to a full-term, healthy infant, recalls that his success generated equal shares of support and condemnation.
"We sometimes get blamed for playing God by helping older women have babies," he says. "But if a cardiac surgeon extends the use of my heart for 20 years by coronary bypass, that's no different from my extending the life of a woman's reproductive system by performing ART."
Ironically, it is advances in the technology that may help put to rest many of the ethical concerns. For example, says Paulson, progress in embryo culture technology-the process through which a fertilized egg is grown in a petri dish before being implanted in a woman's uterus-is eliminating the need to implant multiple eggs and the consequent risk of multiple gestations. In the late 1980s, success rates were low due to the fact that only a single embryo was obtained from a woman during her natural cycle. Pressure to achieve higher success rates lead to developing technology to generate and implant multiple embryos.
During that period, embryos harvested from donors were only nurtured for two days before implantation. Improvements in the methods used to handle fertilized eggs and keep them viable extended the in vitro embryo development time to five days postfertilization, Paulson explains.
This was a crucial development because at five days fertilized eggs reach the blastocyst stage, a desirable goal for implantation. What starts as a single fertilized egg cell (zygote), divides and becomes a small ball of cells (embryo). Additional changes take place over the next few days, including a division between inner cells and outer cells that eventually helps form the placenta, and the secretion of a hormone that helps with implantation, explains Paulson. Because this blastocyst stage is when a fertilized egg enters the uterus in an unassisted pregnancy, success rates are higher when embryos that have reached blastocyst are implanted.
"The fact that it develops to a blastocyst shows it is viable," says Paulson. "By waiting until just prior to implantation, we're able to select the best embryos."
Technology on the horizon will make it even easier to implant only those blastocysts that will develop into pregnancies, he believes. "We now only transfer two blastocysts," Paulson says, "but still half the patients have twins, which, fortunately, most of them like. If somebody doesn't want twins, we only transfer one blastocyst, although that does decrease the chance of success."
He adds, "By looking at the genetic material of the blastocysts, we'll be able to tweak the rate even higher. We will look for high metabolism rates and other subtle clues that will make single blastocyst transfer the right choice for everyone."
New technologies may also make it possible for older women, who must now rely on egg donors, to have babies with their own genetic material. After age 35, a woman's ability to become pregnant with her own eggs becomes more and more difficult, notes Paulson. Generally, IVF success rates decrease with age: by age 40, cycle success is 20 percent and by age 45, it is less than 5 percent. Because of this, many older would-be moms turn to egg donation-where an egg from a younger woman is fertilized with the husband's sperm in vitro, and then implanted in the older woman's uterus.
"Egg donation is not an ideal situation-all women would clearly love to have their own genetic information in their babies, rather than genes from a donor," he says. "However, many women find it a blessing, knowing this is the one technology that still makes pregnancy possible." Of the 200 ART procedures Paulson performed last year, about half involved egg donation. The good news: with egg donation there is an almost 70 percent success rate.
The use of ART has demonstrated that age need not conclusively rule out a woman's ability to carry a pregnancy. Older women whose ovaries no longer produce the hormones needed to sustain a pregnancy are given hormone supplementation. The ideal in ART is to help these older women have babies with their own genes, says Paulson, but "we still haven't figured out how to overcome the age-related decline in egg viability, but it will happen."
Research is now focused on the nucleus of the cell, the site of all the genetic coding that gives a baby the stuff of life: shape, size, looks, function-everything from hair color to propensity for disease. For the older woman whose eggs will not remain viable, cloning technology could be an answer. Making a direct clone of the egg cell might be one answer, Paulson says, making a viable egg from the non-viable one.
In a different approach, one now being tried for the first time, the cytoplasm from a younger woman's egg cell would replace the cytoplasm in the egg cell of the older woman. The composite cell would contain the genetic information from the older woman, who would be the mother of any offspring, passing on her genetic information to her baby.
Cytoplasmic donors instead of egg donors might seem like a perfect solution. But research is finding that the mitochondria that also float suspended in the cytoplasm of a woman's egg cell may have a much larger role than was previously understood. Mitochondria contain genetic material of their own, although the role of this mitochondrial DNA is not clearly understood. Scientists do not believe the mitochondrial DNA to be in the "germline"-that is, traits are not passed on to baby from mother through this means.
What scientists do believe is that the thousands of mitochondria in each cell are vital for cellular energy production and development of a fetus's metabolism. "So the other issue becomes, can we do a mitochondrial transfer? There are studies underway to inject mitochondria into aging cells, but the results to now are not conclusive," says Paulson.
Nor are they without controversy, not the least of which is the notion that the child of such a union would have one father and two mothers.
Men, too, are benefiting from advances in reproductive technology. "In almost 20 percent of infertility cases we need to intervene on the side of the man," says Paulson. That usually means ICSI-introcytoplasmic sperm injection, where sperm harvested from the man is injected directly into the egg. This technology, available only in the past decade, has made it possible for men with extremely low quantities of viable sperm to have children.
Interestingly, the technique is now being used for men who have no sperm at all in their ejaculate. New extraction techniques, says Paulson, allow doctors to access small areas within the testicles where sperm are produced. "All we need is one sperm," he says.
A technology that is currently of high interest-and high controversy-is the use of stem cells to assist in reproduction. Stem cells are so-called progenitor cells found in bone marrow, blood and certain other tissues and have the ability to develop into almost any other type of cell. Intense interest is focused on using stem cells to rebuild damaged or diseased tissues. Research is underway to try to use stem cells to treat heart disease and many other diseases, including Parkinson's and Alzheimer's. Some current research focuses on using stem cells to restore the normal functioning of sperm or eggs. Such advances, says Paulson, might eventually make assisted reproductive technology obsolete.
"Ideally, you hope that the need for this technology is eliminated," he says. "That's unlikely because there will always be accidents, acts of God, that interfere with a person's ability to have a baby. But I do think the whole fertility puzzle of how to help people become pregnant will be solved and we'll be able to provide fertility for anyone regardless of diagnosis or age."
He adds, "When you think about the possibilities, they are extraordinary. After all, just a few decades ago ART wasn't even a twinkle in the scientific eye."
For more information about assisted reproductive technology (ART), or to learn more about the Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).