“Some women actually have men on the brain” beckoned the headline from the LA Times on September 27, echoing an article in PLoS One describing the discovery of male fetal DNA in the brains of pregnant women. It was “an astonishing finding,” according to the newspaper, necessitating “a new paradigm of the biological self” according to lead author J. Lee Nelson of the Fred Hutchinson Cancer Research Center and the University of Washington.
I suspect Dr. Nelson was quoted out of context, for the idea of two genetically distinct populations of cells, or their DNA, residing in one individual isn’t new. It’s called microchimerism.
From Mythology to Microscopy
A microchimera (“small mosaic”) is a downsized version of the Greek chimera, a mythical beast that had the head of a lion, a she-goat body, and a dragon tail. Woody Allen redefined chimera in the 1973 film Sleeper as a creature with “the body of a crab and the head of a social worker.”
Medical chimerism arises after a transfusion or transplant, and it may follow pregnancy. Our microbiomes, the bacteria within us, are more like guests than body parts.
Dr. Nelson’s group found Y chromosome DNA sequences in several brain regions in autopsy slides from 37 out of 59 women. Such DNA liberated from fetal cells can come from several sources: children, fetuses that never made it to be born, older siblings, or twins. Both son and daughter DNA partake in this “feto-maternal trafficking,” but female DNA, at the chromosomal level, is harder to detect amid the maternal two X’s.
“It isn’t surprising that Y-bearing cells are in the brain because they’re in lots of other organs. We’d already shown Y sequences in the cerebrospinal fluid of women at the time of delivery. When they had spinal anesthesia, we collected a bit of spinal fluid and assayed it for male DNA,” Diana Bianchi, MD, executive director of the Mother Infant Research Institute and a professor of pediatrics, obstetrics & gynecology at the Tufts University School of Medicine told me. She and her team knew the Y DNA had come from sons because they witnessed the births. Y sequences have also been found in the brains of mouse moms.
A Great Paper — From 1893
The earliest hint of the possibility of fetal remnants in maternal bodies is in a 1893 publication by German pathologist Georg Schmorl. Dr. Bianchi and her colleagues offer a “21st century re-appraisal” of the paper in the journal Placenta.
Dr. Schmorl autopsied 17 women who’d died during or shortly after childbirth, from the convulsions of eclampsia. “Very peculiar” big, blobby, cells had lodged in the tiny blood vessels snaking through the women’s lungs, and elsewhere. The odd cells were merged, their nuclei nestled at the centers like clutches of frog’s eggs.
The cells resembled cells from only two places: bone marrow or placenta. Because there wasn’t evidence the women had bled, the placenta was a more likely source, Dr. Schmorl hypothesized. Could powerful uterine contractions have shaken the cells loose, like an earthquake toppling bricks from a wall? He wondered if placental cells also slip into the bloodstreams of healthy pregnant women.
To test his hypothesis, Dr. Schmorl made a placenta soup from rabbits and dogs, and injected the material into other animals. Most of them died, usually from convulsions. And most had clots, typically in the blood vessels of the lungs. Just like the women.
Fetal Cells in Moms Are Common
Jump to 1969. A paper in The Lancet reported Y chromosomes in the bloodstreams of 21 of 30 pregnant women; 19 of the 21 delivered boys. The other 2 women had older sons who could have left genetic remnants of their time in utero. In those days before use of fluorescent DNA probes to clearly distinguish chromosomes, Janina Walknowska and colleagues painstakingly eyeballed the one cell in thousands that picked up crude stains for the tiny yet distinctive Y chromosome.
In 1979, Dr. Bianchi and her group used fluorescence-activated cell sorting to detect cells bearing surface markers from the father, representing the fetus, in the blood of pregnant women as early as 15 weeks. This work complemented the Y chromosome study.
Then in 1996, the Bianchi group found that fetal-to-maternal microchimerism persists well past pregnancy, something probably evident in Dr. Schmorl’s slides, had he the tools to look. The researchers looked at surface antigens and Y-chromosome DNA sequences in the blood of 32 pregnant women and from 8 nonpregnant women. The eight who weren’t pregnant had all had sons, 6 months to 27 years prior.
Of the 19 women who had sons, 13 had male DNA. Four of the 13 women who delivered girls had male DNA, which came from pregnancies past — 2 sons and 2 terminations. Six of the 8 nonpregnant women had male DNA, including the mother of the 27-year-old man.
The conclusion: pregnancy sets up “a long-term, low-grade chimeric state in the human female.” And because it happens more often than not, the fetal cells are probably adaptive, perhaps dampening the pregnant woman’s immune response against the fetus.
Fetal blood cells are found in the circulation of a quarter of pregnant women during the first trimester, and in 40 to 70% of them by the third trimester. I, with three daughters and no brothers, lack the Y-tagged variety. My brain is free of male DNA and that must be why I hate football and readily ask for directions.
Non-Invasive Prenatal Testing
Cells aren’t the only signs of a fetus — on average, about 10% of the free-floating DNA fragments in a pregnant woman’s bloodstream come from the fetus – and only the one currently in residence, not from a prior pregnancy. These pieces are perfect for prenatal testing.
At least three companies already offer such tests, called NIPT (non-invasive prenatal testing). Ariosa Diagnostics, Sequenom, and Verinata Health. They use two approaches (massively parallel signature sequencing and directed analysis) to spot two or three of the most common trisomies (13, 18, and 21). The California Technology Assessment Forum is currently evaluating the impact of NIPT. Early reports indicate that the approach can indeed successfully stand in for riskier amniocentesis.
It’s even possible to amplify and overlap cell-free fetal DNA from maternal bloodstreams to assemble full fetal genomes. And it all circles back to the 1893 report, because women with pre-eclampsia have five times the normal amount of cell-free fetal DNA.
The Body Turning to Stone
I was familiar with fetal cells in maternal bodies not in the blood or brain, but in skin. In 1998, Carol Artlett, then at Jefferson Medical College, discovered fetal cells and DNA in the skin of women suffering from systemic sclerosis (aka scleroderma).
Patients, most of whom are women between ages 45 and 55, describe the connective tissue disorder as “the body turning to stone.” Joints swell, fingers stiffen, and the face becomes masklike. The hardening may spread to the lungs, esophagus, and blood vessels.
Several clues point to fetal cells inappropriately stimulating the maternal immune response in the disease:
• Systemic sclerosis is much more common among women.
• Symptoms resemble those of graft-versus-host disease (GVHD), in which a transplant attacks the recipient’s body. A fetus is like grafted foreign tissue.
• The cell surfaces of mothers who have systemic sclerosis and their sons are more alike than those of unaffected mothers and their sons. Did fetal cells similar to those of their mothers-to-be lie beneath the radar of her immune surveillance, persisting silently in the skin until some unknown event uncloaked them?
The discovery of fetal cells in maternal skin revealed a novel way to develop an autoimmune condition, and that’s why the PLoS One paper didn’t seem like news to me. But I can understand why finding male DNA in female brains made headlines.
It would be nice, though, if, in the haste to disseminate or package news, reporters could look to the past. They’d find that nearly all medical “breakthroughs” – from transplants to chemotherapy to monoclonal antibodies to gene and stem cell therapies and even to yesterday’s news about tinkering with the mitochondrial DNA in human eggs -– took years, even decades, and the efforts of many scientists, not one or two groups. (I think I’m a little more sensitive to news not being new because I write textbooks.)
Tracing the backstory can be just as intriguing as reporting the news.