Bringing up baby's DNA: less risky techniques for assessing fetal genes.
Three years later, Nolan has not only a perfectly normal son but also a healthy, 5-month-old daughter. Their well-being wasn't just a pleasant surprise. Like many older mothers, Nolan opted early in each pregnancy to have a procedure called amniocentesis, in which a doctor uses a thin needle to draw fluid from the sac that surrounds a fetus. Fetal cells floating in this liquid hold a developing baby's DNA and so give doctors the means to get a precise readout of genetic disorders that a fetus might have.
Both amniocentesis and another procedure called chorionic villus sampling, in which doctors pluck bits of the placenta, isolate fetal cells that can reveal many genetic problems in an unborn baby with near certainty. But both procedures come with some risk because they invade the pregnant woman's uterus. Out of every 100 women who undergo these procedures, 1 or 2 will have a miscarriage.
"I weighed the odds and thought it was more important to find out what was going on with my baby than whether I miscarried," says Nolan.
Although the gamble paid off for Nolan, this risk isn't acceptable for some women. Researchers are developing new ways to harvest babies' genes in less risky ways--for example, from fetal DNA floating in a mother's blood or from cells that have detached from the placenta and lodged in her cervix. Scientists have a few hurdles to overcome before tests based on these techniques become routine, but safely learning about their baby's health in advance could put morns and dads a significant step ahead in preparing for parenthood.
ROAMING FREE Amniocentesis and chorionic villus sampling are currently the only way doctors have for analyzing a fetus' genes, but scientists have for decades been contemplating how to replace these tests with less invasive ones. In the late 19th century, scientists found what looked like placental cells in the lungs of women who had died from preeclampsia, a condition that creates high blood pressure during pregnancy.
In the 1970s, researchers identified the vehicle that delivers these cells to the lungs. It's a pregnant woman's blood. But they found that only about two to six fetal cells, such as immature red blood cells and immune cells, circulate in every milliliter of maternal blood.
Prenatal-genetics researcher Diana W. Bianchi of Tufts University in Boston made one of the earliest attempts to harvest these cells. Using an antibody that binds to a protein found mostly on the surface of fetal cells, Bianchi and her colleagues showed in 1990 that they could pluck out a few of the precious cells floating in samples of a pregnant woman's blood. But since these cells are so rare--virtually undetectable in some women--and tricky to distinguish from a mother's own cells, Bianchi and other researchers put these circulating cells on the back burner as a new source for genetic testing.
A major advance came in 1998 when Dennis Lo, now at the Chinese University of Hong Kong, and his colleagues reported that fetal DNA circulates freely outside of cells in a pregnant woman's bloodstream. Lo notes that this genetic material seems to make its way into maternal blood when placental cells die, rupture, and spill their contents into the mother's bloodstream. Studies have since shown that about 20,000 placental cells die per minute under normal conditions. Even more DNA enters the mother's bloodstream when she or the fetus has certain health problems, such as preeclampsia or Down syndrome.
Lo notes that circulating fetal DNA sticks around for several minutes in a mother's blood, providing ample time for researchers to harvest the genetic material for prenatal tests. The tricky part, he adds, is separating the baby's DNA from maternal DNA that also floats in the bloodstream.
"It's easy if the baby is a boy--then you can just use the Y-chromosome as a marker," says Lo. To make the tests usable for girls, he adds, "we need to find something else that's fetal specific."
In the Oct. 11, 2005 Proceedings of the National Academy of sciences, Lo and his team reported on a novel way to differentiate a baby's DNA from its mother's. The accomplishment took advantage of a phenomenon called epigenetics, in which chemical modifiers, such as methyl groups, attach directly to DNA and regulate gene activity (SN: 6/24/06, p. 392).
Since epigenetic modifications can change with a person's age, Lo and his team wondered whether they could find some genes that are methylated differently in a fetus than in its mother. After searching through thousands of candidates, the researchers focused on Maspin, a tumor-suppressing gene that's active in the fetal cells of a placenta but not typically in a mother's cells. Lo and his colleagues found that the gene is usually methylated in a mother's blood but unmethylated in the placenta.
In subsequent tests, the researchers found that they could detect fetal DNA with unmethylated Maspin in all three trimesters of pregnancy. Using their new technique to reveal excessive fetal DNA in some mothers' bloodstreams, the researchers reliably predicted which women would develop preeclampsia.
The team plans on looking for epigenetic markers that might disclose the presence of specific diseases of the fetus, such as Down syndrome. That disease is marked by three copies of chromosome 21, but the phenomenon can currently be detected only by examining whole fetal cells.
Recently, a team of scientists led by molecular biologist Sinuhe Hahn of University Hospital in Basel, Switzerland, discovered another way to reliably separate fetal DNA from maternal genetic material. The researchers made the chance discovery that circulating bits of a baby's genetic material are significantly shorter than a mother's. Though the researchers aren't sure why that is, one idea is that the high rate of turnover among placental cells might shatter long strings of DNA into strands much shorter than those of maternal origin.
In the Feb. 16, 2005 Journal of the American Medical Association, Hahn's team showed that separating circulating DNA on the basis of size could provide a new way to test for genetic disease in a fetus. The researchers took blood samples from 32 pregnant women carrying fetuses at high risk of beta-tha-lassemia, a genetic disease that causes severe anemia. The scientists separated the circulating strands into short and long strands and then tested the batch of shorter strands for four mutations known to cause the disease. Checking their findings against chorionic villus sampling, the researchers identified the mutations in the circulating fetal DNA with almost 100 percent accuracy.
Hahn and his team are currently working to expand their findings into tests for other genetic conditions.
CELL SOLUTION Although much of the work on new prenatal tests now focuses on circulating fetal DNA, some scientists still see plenty of promise in the whole fetal cells found in maternal blood and elsewhere.
If researchers find a reliable way to isolate enough fetal cells, they could be more useful than circulating fetal DNA, says cell biologist Esther Guetta of Chaim Sheba Medical Center in Tel-Hashomer, Israel. For example, for a recessive disease such as sickle cell anemia, in which two copies of a problem gene are packed in each cell, it's difficult to distinguish whether a copy circulating in the blood belongs to the fetus or the mother. That wouldn't pose a problem if researchers had whole fetal cells to work with, Guetta notes.
"If you have the whole cell, then you know that all the fetus' DNA is compartmentalized in that cell," Guetta says. "[Cell free] DNA is important, but it won't answer all the questions."
She and other researchers have identified several different types of fetal cells, such as immature red blood cells and stem cells, that circulate along with placental cells in a mother's bloodstream. Her team is tackling the problem of fetal cells' rarity in maternal blood by developing methods to grow those cells into easy-to-test colonies in the lab.
In the March 2005 Journal of Histochemistry and Cytochemistry, Guetta and her colleagues showed for the first time that circulating placental cells could multiply in the lab. Starting with blood samples that held only one or two fetal cells per 20 ml of blood, the researchers placed the cells in a specially crafted mixture of nutrients and proteins to increase this number about five-fold over the course of 5 to 7 days. Guetta's team used these new cells to predict a fetus' gender with about 93 percent accuracy.
Joe Leigh Simpson of Baylor College of Medicine in Houston and his colleagues are currently investigating how to make use of another promising source of fetal cells: the mucus plug that fills a pregnant woman's cervix. Besides shedding cells into the bloodstream, the placenta deposits cells into this mucus plug, notes Simpson.
"The attraction is that there are lots of cells there," he says. Having such cells harvested would be "like having a Pap smear," he adds, referring to the simple procedure that many women have once a year to check for cervical cancer and other health problems.
However, Simpson notes that several challenges must be overcome before harvesting cells from the mucus plug is practical for prenatal testing. For example, it isn't easy to extract the fetal cells from the thick, sticky mucus--researchers need to identify chemicals that dissolve this type of mucus without killing the cells. Also, since many maternal cells are mixed in with the fetal cells, researchers must come up with a way to distinguish a baby's cells from its mother's. Working with a company called Biocept in San Diego, Simpson and other researchers are testing several promising solutions to these problems.
BUNDLE OF QUESTIONS As scientists move closer to developing genetic tests that match the reliability of amniocentesis and chorionic villus sampling but lessen their potential harm to a fetus, some researchers expect that more women will choose to undergo prenatal testing. That's likely to raise the possibility that more mothers will hear that their unborn baby has a worrisome genetic condition, says Brian Skotko, a Harvard researcher who specializes in medicine and public policy.
"It's not inconceivable that in the future, a woman will be able to get a preganancy test and at the same time find out if her baby has Down syndrome or another disability," he says. "It definitely opens a new avenue in the [obstetrics and gynecology] world with ethical and personal questions."
One of those questions that Skotko recently investigated was how doctors should tell a mother that she is carrying a child with Down syndrome, which currently affects about 350,000 people in the United States. In the January 2005 Pediatrics and the March 2005 American Journal of Obstetrics and Gynecology, Skotko published two studies that concluded that doctors often tell mothers about their baby's diagnosis in an overwhelmingly negative way, using insensitive language and focusing on the hardships and limitations that their child may face. Doctors also frequently assume that a woman carrying a child with Down syndrome will want to terminate her pregnancy.
Nowadays, that's often not the case, says Skotko. Medical advances and society's changing perceptions have greatly improved the quality of life for people with Down syndrome and many other congenital conditions--and for their parents. Nevertheless, if tests can safely spot a fetus' genetic problems, more parents will have a chance to plan for their family's future, whatever they choose.
Says Skotko: "More parents will eventually need to decide, 'Is this life valuable?' It's a tantalizing question that's a profoundly personal one."
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|Title Annotation:||deoxyribonucleic acid|
|Date:||Jul 22, 2006|
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