Tufts' Diana Bianchi and her research team have found that fetal cells may be the key to repairing diseased or injured tissues.
When a little kid gets a finger cut, it's no big deal. After a quick bout of tears, the ceremonial application of a Band-Aid and a day or two of time gone by, the cut is healed, and new, gleaming pink skin shows where the injury occurred.
The reason for the speed with which a child's skin repairs itself, compared with an adult's laggardly, drawn-out process, is simply that a child's cells are young, fast and efficient at what they do. Young cells don't dally or think twice about what shoes they should wear. Instead, they fly to the spot where the repair is needed and make short work of the job. They do their work seamlessly.
Now imagine if an older person's body contained a batch of these younger, fresher cells. Imagine if they could be held in reserve for when they were needed and then deployed in a flash to save the day when the older person got hurt or developed a disease. Wouldn't that be great - something like Superman flying in at the speed of light, the ultimate rescuer, poised, selfless and unstoppable?
That unlikely scenario of young cells hiding out in the mom's body until they are needed is just what Dr. Diana Bianchi believes she has found through her recent research into fetal cell migration. Bianchi is the Natalie V. Zucker Professor of Pediatrics, Obstetrics and Gynecology and vice chair for research in the department of pediatrics at the Floating Hospital for Children.
Bianchi has been tracking fetal cells in the mother's body for years, beginning with her hunt for a better prenatal diagnostic tool than amniocentesis, a common invasive procedure carrying small but irreducible risks.
Her hope for the prenatal test hit a wall when fetal cells in maternal blood proved both exceedingly rare and hard to isolate - "not a needle in a haystack but a needle in hundreds of haystacks," in the words of a British colleague. But Bianchi hadn't wasted a lick of her time. In the mid-1990s she was the first scientist to determine that fetal cells remain in the mother's body for many years, perhaps indefinitely, after a pregnancy, whether that pregnancy is carried to term or not. "A pregnancy lasts forever," she suggests, "because every woman who has been pregnant carries these little souvenirs of the pregnancy for the rest of her life."
More recently and thrillingly, with the publication of their breakthrough article last summer in the Journal of the American Medical Association [JAMA] ("Transfer of fetal cells with multilineage potential to maternal tissue," July 7, 2004), Bianchi and her team demonstrated that these fetal cells may be there for a reason. They seem to play a therapeutic role in the life of the mother. If the woman suffers a wound or develops a disease in an organ even decades after being pregnant, the fetal cells in her body migrate to the site of the injury, divide and change into the perfect cells needed to fix the problem. Fetal cells provide, in effect, a long-term life insurance policy for the mom.
"Whatever the mechanism involved," Bianchi and her co-authors wrote toward the end of the JAMA article, "we believe that the idea of fetal cells expressing non-hematopoetic markers [i.e., cells capable of changing from precursor cells to cells needed in a specific organ] is novel and may have important long-term implications for the woman who has undergone pregnancy by providing her with a younger population of cells that may have different capabilities in the response to tissue injury."
Consider what's being said here, ever so quietly. Bianchi's findings stand the familiar one-way model of maternal nurturance on its head. Mom feeds and sustains her baby during pregnancy by means of nutrients that flow through the umbilical cord to the developing child - understood. But that's only half the story. It turns out that the umbilical cord is a two-way street, and the nurturing process goes both ways. Beginning early in the pregnancy, the baby is sending fetal cells back into mom, where her body stores them, like pin money saved for a rainy day.
The implications of the mysterious process Bianchi has glimpsed are just now becoming visible to other experts in the field. "Diana's work on fetal cells is incredibly exciting and contrary to expectation," says Dr. Judith Hall, professor of pediatrics and medical genetics at the University of British Columbia and a former president of the American Society of Human Genetics. "Nobody ever suspected that these cells stayed around. It's a shock." Then, with regard to the immense second shoe that has thumped onto the floor in the past year, she adds: "If babies can help their moms survive, that's a good deal. The idea raises amazing possibilities."
Hang your hat
Diana Bianchi has always been captivated by the whole entrancing business of pregnancy and birth. She remembers, at age four, watching with fascination as a cat gave birth to kittens under her bed. "It was so interesting," she says, still sounding a bit unsettled by the experience.
Bianchi grew up in New York City. Her father, an economist by training, ran a local country club, and her mother was a stage actress who appeared frequently in off-Broadway shows. "My brother and I never had babysitters - we always got taken to rehearsals instead," Bianchi jokes. "We grew up painting scenery."
She left the showbiz glitz behind when she went off to study biology at the University of Pennsylvania, where one of her mentors, Nobel laureate Baruch Blumberg, known for his discovery of the hepatitis B virus, remembers her as an "outstanding and enthusiastic" student. Bianchi graduated from Penn magna cum laude in 1976 and entered Stanford Medical School the next year.
It was there that she began her hunt for a kinder, gentler blood test to detect chromosome abnormalities in fetuses: "I wanted to find better information about fetal health." Her first efforts focused on developing a prenatal blood test to detect Down's syndrome.
Her approach of examining fetal cells in maternal blood didn't pan out. The cells were just too difficult to isolate. Bianchi next turned her attention to fetal DNA in maternal plasma. A chance discovery in 1995 pointed Bianchi's research team in still another direction.
"If we can prove these are stem cells and harvest them from the blood or tissue of a woman who's been pregnant, they could have therapeutic potential for that woman, her children and perhaps even unrelated individuals," says Diana Bianchi.
The team accidentally detected long-term persistence of fetal cells in maternal blood postpartum. No one expected this finding, and - according to the ancient unwritten law of science which states, "If I Didn't Think of It Already, It's Probably Not True" - many authorities in the field doubted her conclusion. Bianchi had considerable trouble getting her paper published in a respected medical journal. "I still have the rejection letters," she is quick to say. "The idea seemed crazy."
However odd, the persistence of the cells postpartum immediately raised the million-dollar question: What the heck are they doing there? Three main possibilities came to mind, and these same three continue to hover over the new scientific field of "microchimerism" - that is, the presence of cells from more than one individual in a single person - that Bianchi's finding helped to introduce. Are fetal cells hanging around to help the mother somehow? Might they be doing damage within mom's body? Or are they innocent bystanders, making absolutely no difference one way or the other?
In the JAMA article from last summer, Bianchi and her research team began by conceding that fetal cells have been observed in higher numbers in women with certain autoimmune diseases such as systemic sclerosis than in control groups. However, as the authors of the study went on to note, fetal cells also have been seen in the tissues of women with non-autoimmune disorders - ailments such as hepatitis C and cervical cancer. "Thus," the researchers nicely conclude, "we developed an alternative hypothesis in which fetal cells were associated with the maternal response to injury as opposed to causing disease."
You could hang your hat on that sentence. As lead author, Bianchi has sidestepped a world of presumption in this single line and veered off on her own. People who know her well aren't much surprised.
"She's always three steps ahead of the game," says Nicholas Fisk, senior clinician-scientist at the Institute of Reproductive and Development Biology at the Imperial College School of Medicine in London. Fisk's lab is known for having studied a group of British grannies who had had boy children and discovering fetal cells in their bone marrow up to 51 years postpartum, the latest detection of these cells to date. "We think they reside there forever," he says.
Waves breaking on the shore
Boys rather than girls are the focus of Bianchi's and Fisk's research for a pragmatic reason: The male chromosome, with its dangling Y, shows up better in the mother's body and is quicker and easier to track, standing out as it does from maternal blood and tissue. Looking for a girl's fetal cells in her mom's body would be like searching for snowflakes in a snowstorm - sure, you could do it, but why would you want to? Scientists in the field presume that everything they have discovered about the persistence and function of male fetal cells applies equally to female fetal cells.
For the research that ran in JAMA, Bianchi and her team sought to test the idea that fetal cells helped women cure themselves. They selected 10 women, ages 34 to 74, who had borne male children and whose bodies were under assault from one disease or another. Then they created a control group of 11 women who had comparable diseases but who had not given birth to male children. The results were dramatic. In the first group, without exception, diseased maternal tissues showed the presence of transformed male cells. In the second group, no male cells could be found at equivalent sites.
One woman in the first group had hepatitis C, a viral infection, but when her liver repaired itself, it used cells that were not her own. "Her entire liver was repopulated with male cells," Bianchi told a reporter from The New York Times. The inferences of the find are stunning.
Although these fetal cells sure sound like stem cells, Bianchi is careful not to use that term until she can isolate them and prove that they can turn into any of the body's specialized cells. Until then, "a fetal cell population with the capacity for multilineage differentiation," the language used in JAMA, will have to do.
Could fetal cells buried in maternal bone marrow some day be tapped as a mine of riches to help treat a raft of common human afflictions like Parkinson's and Alzheimer's diseases? Bianchi is hedged but hopeful in her reply. If these cells are true stem cells, she says, the nifty thing is that they can be retrieved without the ethical firestorms normally associated with obtaining fetal material. They could be extracted from maternal blood or tissue, both considered ethical sources, thus rendering the use of human embryos unnecessary.
All research is tentative and prone to revision. The waves of fetal microchimerism are just beginning to break along the scientific shore. It's early yet, and not everyone can see them coming in. But it's fair to say that Bianchi, a world leader in the field, can taste the possibilities as well as anyone.
Profile written by Bruce Morgan
This story originally ran on June 20, 2005