The Female Advantage
WHEN ZOLTAN SPOLARICS talks about his research on X chromosomes — tiny pieces of twisted, cellular DNA and protein — and the unique differences between males and females, everyone routinely responds with the word, "Wow." This Hungarian-born scientist leans forward in his chair and his enthusiasm is contagious. He's into basic and tantalizing questions about biology here — male versus female — and he knows it.
"I got here by accident," he explains. "I was studying genetic polymorphisms of metabolic enzymes and cytokines and their effect on the immune system." It turns out that the impact of any genetic polymorphism (small individual differences in the genetic code) is different if the gene you are studying is X-linked, or located on the X chromosome. This is because the "behavior" of the X chromosome in males and females is "trickier and a little more complicated" than other chromosomes. The X chromosome carries many more genes from one generation to the next (1,098 to be exact) than the male Y chromosome (78). "Everybody was studying the impact of polymorphic genes located on non-sex chromosomes but the X chromosome was being neglected. This is just one of the reasons why I like this area of research. Here was this new, exciting and impressive question of how sex regulates biology and the more I read the more excited I got about the X chromosomes. I could build a really exciting and novel hypothesis around this. But it was also lonely and scary at the start," Spolarics admits.
|ZOLTAN SPOLARICS, MD,
PHD, NJMS, GSBS,
A professor in the UMDNJ-New Jersey Medical School (NJMS) Department of Surgery, Spolarics earned his MD at Semmelweis Medical School in1980 and his PhD at the Hungarian Academy of Sciences in 1986. He fell in love with America during a post-doc in the Department of Biochemistry, Medical College of Virginia, and later as an assistant professor at the Department of Physiology at Louisiana State University Medical Center in New Orleans. "New Orleans was a nice city but it was also a partyall- the-time kind of place," not the perfect atmosphere to raise children. He joined NJMS in 1993 to investigate the immune systems of critically-injured patients and he was among the first researchers to point to the potential impact of genetic polymorphisms in the clinical outcome of trauma patients. He chuckles about the fact that when he was entering medical school, one of his mentors insisted that DNA would take "us nowhere because it is too big and difficult to isolate. Now," laughs Spolarics, "it is just shocking how sophisticated this field has become and how much we have learned as a result of decoding our DNA."
While it has been proposed that the way X chromosomes are biologically configured may play a role in autoimmune diseases, which are more frequent in females than males, what was scary for Spolarics was that no one else, to his knowledge, was, or is, looking at whether the gender differences in the X chromosomes relate to why women have a better general health status and an improved innate-immune response to infection and injury than men. "When I first started, because I'm not a geneticist by training, I wondered, ‘What am I missing? Why is no one else studying X chromosome differences in the context of gender and the host response?'" Many studies addressed gender differences but only from the hormonal aspect. The Spolarics lab has a grant for $1,166,880 from the National Institutes of Health (NIH) to find out how and why the female X chromosome works its clinical magic. "Females show better general health and longer life span than do males and even in a variety of conditions, including infections, women do better than men," he explains.
While Spolarics is only at the proof of principle, or early stage of the work, he explains that sex hormones can't be the only reason for this female advantage in life because both pre-pubertal girls and post-menopausal women (when hormones shouldn't really be part of the puzzle) do better than their male counterparts. For Spolarics, it's got to be the unique properties of the X chromosomes which contribute to these gender-associated differences in physiology, pathophysiology and disease progression. In fact, what he knows is that the X chromosome carries a large number of genes specifically encoded for proteins whose central function is in immunology and the kind of metabolic systems that play critical roles in survival and shock responses.
In every single cell, women carry two X chromosomes, one from their mother and one from their father and their cells express either one or the other, while men inherit just one X from their mother along with one Y from dad. "Whatever X chromosome a man gets from his mother, ‘good or bad,' that's what he's stuck with," a fact that explains why men are more likely to manifest a severe X-linked genetic defect than women. If a female inherits a deficient X-linked gene, it impacts only half of the cells. Meanwhile, the other half expressing the normal gene can compensate for the lack of function in the deficient one.
Thus, women are a cellular mosaic, or mixture, of their two types of X chromosomes, part of their mother or part of their father in their cells. Half of the cells in females are fine-tuned by the genetic variations from mom's X chromosome, while the other half of the cells are fine-tuned by the variations unique to dad's X chromosome. And the presence of this mosaic parental subset is at the heart of the female advantage. The extra medley of X-linked cellular variability is a "more responsive, or adaptive, system," Spolarics says, that will be available during the host response to injury or infection which are dynamically changing functional conditions.
In his most recent study published in The Journal of Immunology which investigated an X-linked protein that helps out when bacteria need to be killed, Spolarics showed that "mosaicism presents its own phenotype and provides improved antibacterial defense." The responses of mosaic cells within a subject are measurable and exactly what the Spolarics team is currently looking at in animal models to learn why and how mosaic-celled females present improved outcomes as compared to single X chromosome-expressing subjects, like males.
An inflammatory response is a dynamically
changing physiological condition during
which cells are continuously multiplying,
dying, getting activated or paralyzed. The
broadened functional variability in mosaic
females accommodates better to these tough
conditions. "When one cell dies, the other
takes over," Spolarics says. He is willing to bet
that understanding these differences between
men and women will add to more meaningful
approaches to medical care for both sexes. He
believes that medical practice will move
towards an era of more personalized medicine
when one size doesn't fit all especially in
complex, pathophysiological responses such
as multiple trauma or polymicrobial sepsis.
According to Spolarics, to increase the
chances of surviving an accident or illness, or
to fight sepsis when the body's own defense
system may become a killing machine, is
never going to require a single molecule or
gene as a therapeutic target. What is needed
to alter such a cascade of events is a whole
"set of genes and interactions." And in the
meantime, this gifted researcher is getting a
much clearer picture of the mighty, maternal
— Maryann Brinley