Microchimeras and Serotonin

While many of the claims at improving cognition are dubious (eg, the "Mozart effect"), there is now ample reason to suspect that parental involvement in children's brain development occurs much earlier than the first 3 years. Data now suggests that maternal cues are critical to proper brain development long before birth. In this article, I will explore this almost ridiculous example of early parenting, including the strange world of microchimeras and the role maternal serotonin plays in fetal brain development. I will begin with some information about chimeric biology and then move to data involving brain development in laboratory animals.

In Greek mythology, Chimera was the name of a fantastic fire-breathing female monster who looked as if she were created by a committee. Her front part was usually depicted as a lion, her back end was a dragon, and her middle was a goat. She was a mythological creature of great destructive power.

As genetic and tissue engineering techniques became regular practice, the mixed-up characteristics of the Chimera were co-opted by the research community; they used the name to describe a very valuable—and equally mixed-up—biological phenomenon. Chimeras are now formally defined as any organism, organ, or body part made up of 2 or more tissues of differing genetic composition. This can result from grafting, genetic engineering, or even organ transplantation. The word is even used to describe molecules. Antibodies made from the proteins (or genes) of 2 or more different species, for example, are formally termed "chimeras."

It has become clear that chimeric characteristics are not just epiphenomena from research laboratories and clinics. A number of years ago it was shown that during gestation the human fetus acquires chimeric characteristics. Maternal cells get into the fetus and become an active part of its biology, extending into adulthood. Fetal tissues return the favor, entering the mother before birth and setting up shop. Such trafficking has potentially powerful consequences, from embryonic development to immune system reactivity.

More than a decade ago, a strange observation was made in umbilical cord blood samples from male infants. About 20% of the samples contained fetal cells. These results called into question the long-held assumption that maternal cells rarely, if ever, passed into fetal circulation. More refined techniques using DNA showed the incidence to be quite common: 40% to 100% of the samples showed the exchange.

Critics argued that the data could be explained by maternal-fetal exchanges during labor. Their arguments were mostly silenced when fetal blood from second- and third-trimester pregnancy terminations revealed the same chi- meric phenomenon. Indeed, exchanges were occurring throughout pregnancy and appeared to be a normal part of gestation.

Beyond that, the phenomenon was shown to be stable, with maternal cells persisting into adulthood. The idea generated a great deal of excitement. As researchers bore down on the phenomenon, it was shown that the exchange could be 2-way—fetal cells were also found to persist in the mother. Microchimerism appeared to be a normal part of pregnancy.

There are many powerful consequences of microchimerism. One is the generation of autoimmune diseases, demonstrated most notably in systemic sclerosis (scleroderma). The phenomenon has also been linked to autism, phenylketonuria, and irritable bowel syndrome.

One of the most intriguing hypotheses, however, has to do with normal development. Why would the fetal-maternal interactions, previously thought so impossible, turn out to be so prevalent? Why doesn't everybody suffer from some kind of immunological meltdown, especially women who bear more than one child? The answer is a bit of a shocker. It is very possible that, immune issues aside, the exchange is critical for the successful transit of a baby through gestation.

Just how consequential this exchange can be to normal growth has only been recently appreciated. There may even be psychiatric consequences. Two examples—one from humans, one from mice—give a strong glimpse into the powerful role cellular exchanges play in normal fetal growth. At least in mice, this may include brain development.

The first example involves human tissues and the investigation of type 1 diabetes mellitus (T1D). T1D is the archetypal pediatric autoimmune disease, and its origins have been under intense investigation for decades.

Some researchers have suspected that the origins of T1D involve microchimeric activity (maternal-to-fetal exchanges), and a group in Seattle decided to investigate.¹ There was ample precedent—maternal cells have been shown to persist in immune-competent children in a wide variety of tissues, including the thymus, skin, thyroid, liver, and heart. They even survive in the peripheral blood of adults.

The researchers first had to develop a bulletproof assay for the detection of maternal cells in the infant. Finding fetal cells in the mother is fairly easy, especially if the fetus is a male. One simply looks for the presence of a Y chromosome. Discriminating maternal cells from fetal cells in the fetus, however, is a harder task. For that you must use quantitative polymerase chain reaction (PCR), assaying for genes that are nontransmissable and maternal-specific.