Vol.1. No. 2
Cells reproduce by dividing, a simple sounding strategy - but how do they manage to get everything in the right place at the right time.
In our biological age, the basic facts are almost commonplace. The cell carries its marching orders in its DNA. Before the cell divides, the DNA is replicated and packaged in the form of chromosomes. During division, each new daughter cell receives one complete set of chromosomes, providing each cell with the complete genetic information necessary for life and for continued cell replication.
But what orchestrates this reorganization'? What separates the two sets of chromosomes and sends each to its own part of the cell?
Oddly enough, no one really knows how the cell manages this feat of near-total reorganization.
Biologists do know that in order for one cell to become two, a number of exquisitely timed changes must take place. The nuclear membrane must be broken down and the replicated chromosomes must be brought into line. The old cytoskeleton, a network of filaments and fibers that gives the cell its shape, must be disassembled and new, transient structures must be built: a mitotic spindle must be constructed to separate the chromosomes and guide them to their new locations. But what powers all this movement? What provides direction?
More than a century ago, biologists discovered a mysterious little structure (now called a centrosome) that appears to play a central role in reorganizing the cell's cytoplasm and segregating the cell's nuclear contents. Most cells have one centrosome, which is replicated shortly before cell division. During division, the two centrosomes migrate to opposite sides of the nucleus. Lovely, star-shaped asters form around the wandering centrosomes, and then a spindle appears spanning the space between the two centrosomes. Cell biologists have long assumed that these transient structuresÑ collectively called the mitotic apparatusÑhelp to tease apart the chromosomes and to guide them to their new positions.
The asters and spindles are composed of microtubulesÑsmall cables, made of a protein called tubulin, that are found throughout the cell's cytoplasm. But the hundreds of other proteins in the centrosome are still unknown. And the process of centrosome replication remains a mystery.
Getting the centrosome out of the cell These basic questions about centrosomes have remained unanswered in large part because no one has been able to isolate the structures and to get them working outside of the cell. Until recently, that is. Working as a graduate student in Marc Kirschner's lab at the University of California, San Francisco, Tim Mitchison, the 1990 Nikon Fellow at the MBL, developed methods for isolating centrosomes from cultured cells.
And now Robert Palazzo, a young, year-round MBL scientist, has worked out a method for removing centrosomes from clam eggs. Extracted from the cell, Palazzo's isolated and purified centrosomes go happily about their normal business: organizing microtubules into asters and spindles. With working centrosomes in hand, Palazzo and other biologists can begin figuring out what the structures are made of and how they orchestrate the reorganization of the cell's structural components.
The century-old study of centrosomes is more than an academic exercise; answering the basic questions about these puzzling cellular structures may lead to new cancer therapies. Because cells will not divide unless they have two working centrosomes, anything that interferes with centrosome replication or normal centrosome function is a potential cancer treatment. And given the involvement of centrosomes in cell division, a drug or other treatment that targets centrosome replication might affect only dividing cells, arresting the spread of a cancer without damaging other, normally functioning cells in the same tissue.
Of course, cell division involves events other than the replication of centrosomes and the assembly of the mitotic apparatus. A class of proteins called cycling, discovered at the MBL in the late 1970s and early 1980s, triggers many of the reorganization processes in the dividing cell. First identified in sea urchin eggs, cyclins have since been found in cells throughout the plant and animal kingdoms, and cyclin irregularities have been implicated in some human cancers.
Interestingly, there is good evidence from the work of Kip Sluder, a summer MBL scientist from the Worcester Foundation for Experimental Biology, that while centrosome replication an rising cyclin levels are both essential for cell division, the two events may occur independently of each other. If this is true, Palazzo points out, if the cell has two independent pathways, each involving a series of events necessary but not sufficient for cell division, then the two pathways may offer separate targets for cancer therapies that could be used on an alternating basis.
Palazzo's work offers two other potential medical benefits, both related to centrioles, the two small rods that appear at right angles to each other and form the most distinguishing features of a centrosome. Centrioles are also found at the base of cilia and flagella, the cell's tiny, hairlike structures capable of lashing movement. In humans, ciliated cells are found in the airways, intestines, and oviducts, and flagella are responsible for sperm movement and migration. Palazzo's method of isolating centrosomes provides a supply of centrioles for studies that may determine whether centriole abnormalities contribute to infertility or to ciliary dysfunction diseases.
But the most surprising benefit of studying centrioles may eventually be a new form of birth control. To grasp the connection between centrioles and birth control, keep in mind three facts: ( 1) human cells do not reproduce without centrioles; (2) the dividing cell does not build centrioles de novo (anew), but uses the already existing pair to make the new pair it needs; and (3) the human egg cell does not have its own centrioles, but accepts and then replicates the sperm's centriole pair. A drug or other treatment that would interfere with the egg's ability to replicate the sperm's centriole pair would prevent the egg from ever dividing. Another possibility is a male contraceptive that works by disrupting centriole formation in sperm cells, which would inhibit their ability to migrate to the egg.
Many questions remain to be answered before centrosomes yield either cancer therapies or birth control techniques. But now that the puzzling structures can be isolated, purified, and put through their paces outside the cell, biologists are that much closer to knowing how the dividing cell reorganizes itself.
