Abby Dernburg has been obsessed with chromosomes since graduate school. That obsession has led her to illuminate several of the biological forces that guide the very beginnings of life.
"I've developed a very chromosome-centric view of biology," says Dernburg, a cell biologist at the University of California, Berkeley and Lawrence Berkeley National Laboratory. "Because the chromosome contains the genetic material, its whole purpose is to transmit itself. To do this successfully, chromosomes have to undergo a whole myriad of organizational changes during development, and I want to understand how these changes are executed. This is sort of a 'selfish-gene' way of looking at things, but on a slightly larger scale," she says, alluding to Richard Dawkins's 1976 book proposing that living creatures are just vehicles for transferring genes to future generations.
Dernburg wants to understand the whole picture of what chromosomes do and how they do it. She has focused largely on chromosome behavior during meiosis, the cell division that leads to egg and sperm cells, ever since her graduate work, including an HHMI predoctoral fellowship at the University of California, San Francisco and her postdoctoral fellowship at Stanford University.
Like most cells in the body, the germ cells that give rise to sperm and eggs contain two copies of each chromosome, one inherited from each parent. As a germ cell divides during meiosis, it divvies up its chromosomes so that the resulting sperm or egg cells receive one copy of each. If the chromosomes are sorted haphazardly, future generations of cells could end up with too many or too few of them, leading to birth defects. Down syndrome, caused by an extra copy of chromosome 21, is the most common such disorder in humans.
Every meiotic division begins with each pair of chromosomes meeting and zipping together along their lengths. As division proceeds, the paired chromosomes, or homologs, separate, and one goes to each daughter cell. Although scientists have known for more than a century that this pairing occurs, how chromosomes find and recognize their unique match among the jumble of genetic material inside the cell has remained a mystery.
Beginning with her graduate work on the fruit fly Drosophila melanogaster, Dernburg has been unraveling the mechanisms that guide this chromosome pairing. Most of her findings are based on studies of the nematode Caenorhabditis elegans, whose transparent body makes it possible to watch chromosomes in action. In the worm, special regions of each chromosome, called pairing centers, help the homologous chromosomes recognize one another. Building on that observation, Dernburg's Berkeley team discovered that the pairing centers are also required for the proper zipping together of the homologs, a process called synapsis.
Recently, her group revealed connections between chromosomes and components of the cellular skeleton outside the nucleus. Proteins at the pairing center interact with proteins that span the nuclear membrane and link to these skeletal structures, known as microtubules. The microtubules do not seem to be necessary for homologs to find one another, but Dernburg thinks they may be part of a "kinetic proofreading" mechanism that allows only the right chromosome pairs to remain together. It may be that as the chromosomes start to pair, force generated through the microtubules is enough to separate incorrectly paired chromosomes but not enough to pull apart properly chosen pairs.
So far, the kinetic proofreading model is just that—a model. But developing it has been satisfying, Dernburg says. "For me the synthesis part of science is where you as a scientist really make your mark," she says. "It is both the most exciting and the hardest. You have to immerse yourself in the data and come up with something that is more than the sum of its parts. The kinetic proofreading model was an insight that emerged from our work that I hadn't anticipated." Her goal now is to test the model in living animals and, using high-resolution, three-dimensional microscopy, measure some of the biophysical forces involved.
For a long time, Dernburg's chromosome-centric view was so strong ("I even married a chromosome biologist," she notes) that she viewed the cytoplasm as a support system for the nucleus, there to help ensure that the chromosomes made it to the next generation. With her team's 2005 discovery of the connection between meiotic chromosomes and cytoplasmic microtubules, she's shifted that perspective a bit. "I've had to change my world view as I realized that components of the cell that I care about are interacting with parts of the cell that I previously tended to ignore. This means that I've needed to incorporate the cytoskeleton into my thinking and to view the chromosomes as part of a network that spans different cell compartments."
The newly relevant cytoskeleton will not pull Dernburg away entirely, however. Her lab has begun studying meiosis in the flatworm Schmidtea mediterranea. She plans to take advantage of the flatworm's unusual ability to interconvert differentiated cells and stem cells to examine how chromosomes behave in the two types of cells.
"I am still really focused on the chromosomes," Dernburg admits. "To me chromosomes have a lot of personality. They're where so many of the interesting transactions in the cell are happening. "