Size matters, or so men often joke. But when it comes to chromosomes, women rule.

Indeed, with their double complement of robust X chromosomes, commanding 5 percent of the genome's total DNA, females lord it over the males of the human species, who must settle for a single X chromosome and a very diminutive Y -- with about 1/100 the genetic clout of its counterpart.

For the nonscientist seeking to impress, this disparity is interesting cocktail party conversation. But for UCSF biochemist Barbara Panning, it is the backdrop for one of the most momentous of all genetic events: X chromosome inactivation. "As female embryos, consisting of a few thousand cells, implant themselves in the uterine wall, both of the X chromosomes inside their cells are working. Then suddenly, in a matter of a day or less, one of the X chromosomes just shuts down." Moreover, it is not the same X that shuts down in each and every female cell. Rather the shutdown is split almost evenly, creating a mosaic of cells that, as they differentiate into everything from muscle tissue to neurons, make each female entirely distinct. Why this happens has been clear to geneticists for decades. It is the "how" that intrigues Panning and set her on a journey to the command center of the cell.

But first a little detour. Humans have 46 chromosomes, those banded structures inside a cell formed by DNA. One set of 23 comes from the mother and the other from the father. Most cells divide to ensure a fresh supply, and each new cell contains a duplicate set of chromosomes. This division and duplication process is called mitosis. There are two significant exceptions to mitosis: sperm and egg cells, the sex cells. These divide twice (meiosis), limiting the number of chromosomes in each sex cell to 23. Because men carry both an X and a Y chromosome, sperm carry one or the other. Since females carry two X chromosomes, egg cells always carry an X chromosome. The re-pairing comes during fertilization with the ultimate sex of human offspring determined by whether an X -- or a Y -- sperm fertilizes the egg first. Females then proceed through the same early developmental stages as males. But evolution soon intervenes.

Consider the problem. Chromosomes are home to genes, which carry a code for the creation of proteins. Proteins in turn construct the various components that make us human -- from skin to our immune system -- and manage the internal environment that sustains us. Put another way, chromosomes are the active headquarters site for the gene managers, which both instruct and work in concert with a vast army of different proteins.

If chromosomes are the seat of genetic power, then the X chromosome is one of its thrones. Doubling the X doubles the amount of genetic activity, a level that males, with only a single X, cannot match. Geneticists call this condition "dosage imbalance." This disparity is serious business, creating the potential for differences in structure and composition that could over time, threaten the genetic compatibility of human males and females. So nature made a decision: Restore the balance. Rather than make the single X in males work twice as hard, it inactivated one of the X chromosomes in females instead.

"Once made, it is a fateful decision," says Panning. Even minor mistakes in the shutdown can trigger everything from cleft palate to cancer. Major mistakes are worse: the female embryo dies.

The biochemistry behind such life-and-death evolutionary drama proved an irresistible lure to the Swiss-born Panning, who was recruited to UCSF from MIT three years ago. Since structure is function, Panning and her laboratory team decided to focus upon the control site, namely the nucleus's DNA "package." This package consists not only of nucleic acids (the rungs on the twisting DNA ladder, sequences of which are known as genes) but also of proteins (the ladder rails) and the protein core of the chromosome itself. When wrapped, coiled and looped together into a dense structure called chromatin, all 3 billion base pairs (or ladder rungs) of the human genome can fit into the nucleus's tiny compartment.

Yet, as Panning explains, this DNA wrapping is not uniform. "Some sections are wrapped so tightly that they never open. Others are open all the time. And still others open some of the time." But open to what? The answer is RNA, or ribonucleic acid. RNA is perhaps known best as the molecule that "reads" the genetic code as sections of DNA uncoil and pair off with their RNA counterparts. One type of RNA then exits the nucleus and carries the chemical message to a different part of the cell, where it triggers the production of proteins. Other forms go out and come back, helping to regulate the genes themselves. And as Panning and others have learned, some RNA simply stays home.

For at least one of these stay-at-home RNA complexes, its housekeeping responsibilities are anything but routine. That was not obvious a decade ago when research first pinpointed a section of the X chromosome as the so-called X-inactivation center, the area where the shutdown message is generated. Further experiments isolated the gene responsible (Xist) for sending this message. Additional work revealed the gene's silencing agent: an unusual form of RNA. "The RNA is very large, for one thing," says Panning. But more unexpectedly, Panning adds, Xist RNA does not seem to make a protein. Instead it exists as a "little dot" in the nucleus. For reasons and in ways she and her laboratory colleagues are now trying to decipher, the dot enlarges, silencing the chromosome as it goes. "We don't understand the initiating event or what other proteins are recruited and how this form of RNA may interact with them. What is clear is that the chromatin package is somehow altered, and that this alteration controls, or silences, the genes on one of the X chromosomes." Something is also keeping all this action "local," or inside the nucleus.

Sorting out the details means more than solving a scientific oddity. Determining the complex of proteins recruited in the silencing event could offer an important insight into how to halt cancer. It could also shed some light on the aging process, which, some have theorized, might involve an activation of once-silent regions of the X chromosome. There also is a close connection to stem cell research. "X inactivation must occur before cells differentiate into their many different types." In some ways, inactivation is a quality-control step, and knowing how it works might open up entirely new avenues into stem cell biology.

Panning, who is now ensconced at UCSF Mission Bay's Genentech Hall, welcomes the opportunity to continue her research in a comparatively spacious and new laboratory environment, with colleagues clustered into scientific neighborhoods. Indeed, for someone who studies an inactivation event, there is little silence in her life at the moment. Attribute that, at least in part, to another significant pairing of X and Y chromosomes. Panning gave birth to a son earlier this year.