Andrew Murray stands before his audience on April 30, a pingpong ball in hand. Not to play in a tournament, but to illuminate a point. The professor of molecular and cellular biology is giving a talk in the Science Center about cells and their chromosomes.
Life: A cooperative venture
The pingpong ball is proffered to help watchers visualize a cell and its DNA. The ball is about 2,500 times the size of a cell, Murray explains. And inside the cell are masses of DNA molecules, those famous double helices with their swirls of genes: A, C, T, and G, initials of the four chemicals that encode all living organisms.
Murray next holds aloft a ball of string 100 yards long, inviting the audience to imagine all that string stuffed inside the pingpong ball. A relative mass of DNA – compared to string because of its intertwined strands of ATCG sequences – resides inside nearly every cell. “Like Houdini in reverse,” Murray says, “nature somehow coils this much genetic material inside the cell.” These double helices of DNA roost in the cell’s chromosomes.
So begin the stories of life. These tales can be fascinating, almost fantastic. They can also, of course, be tragic. Much is at stake, every day, since each human being is a cooperative of 10 trillion cells, and many cells divide daily or even more frequently. Every time division takes place, all that DNA has to be copied correctly, or the cooperative could self-destruct.
Good citizens and bad
To keep order, “Cells obey extremely strict rules,” Murray says. On the oversize screen appears a portrait of Emily Dickinson. She’s seated primly next to a diagram of chromosome migration during cell division, or mitosis. Like the intense poet, cells conduct themselves quite properly. In fact, cells are so concerned with orderliness, says Murray, that “if they misbehave in the slightest, they get so embarrassed they kill themselves.” And if they wander too far from their home base, “they get so lonely they die.”
At least, that’s how nice cells behave. Not so with renegades. Like the late, murderous punk rock star, Sid Vicious, whose image now flashes across the screen, cells gone awry become rule-smashers. They reproduce at will, without regard for the cooperative whole.
In other words, such cells are cancerous. “They are extremely careless with their chromosomes,” scolds Murray. Instead of the requisite 46 chromosomes per normal cell, cancer cells may have as many as 80. What’s more, these outlaws “don’t kill themselves in shame” when they break the rules. Instead, they boldly wander through the body, colonizing as metastases.
But it doesn’t take a criminal cell to alter life profoundly. With each fertilized egg, cells begin a furious process of division. Chromosomes, with all their DNA, are replicated at a frenzied pace. If an embryo receives an extra copy of any of its 46 chromosomes, other than Chromosome 21, or if a chromosome goes missing, that embryo will either miscarry or die shortly after birth. If this seed of a human being gets an extra copy of Chromosome 21, the baby will have Down syndrome. Murray promises to get back to the phenomenon of Down syndrome later, as it’s a focus in his current research.
More generally, Murray’s work takes him on a journey toward answering the question: How do cells successfully replicate their DNA over a lifetime of daily division?
Cells have somehow, over billions of years, evolved an enormously clever and complex system of checks and balances that keeps the living organism from melting down at every twist in the replication journey. As part of his research, Murray studies a singular element of this cellular magic, the spindle checkpoint.
The spindle itself is like a self-constructing railroad track. It sends out fibrous lines, blindly seeking chromosomes within the cell. A spindle “knows” it has found a chromosome when it connects with the chromosome’s hubcap-shaped midsection, known as the centromere. If a spindle finds no chromosome in a particular part of the cell, it destroys the dead-end track and sends out a new one, continuing the process until its work is done.
Once a spindle has found its required centromeres, the cell can divide. On the screen, Murray shows a laboratory-made film, which he dubs “Cell Division: The Movie.” “The chromosomes jiggle, they move apart, and the cell divides,” Murray says. Indeed, the audience witnesses tiny, wormlike chromosomes dancing to opposite sides of the cell.
“Now the molecular scissors are activated!” Murray exclaims. These scissors are made up of a protein that cuts other proteins in the cell. “When the cut is made, the centromeres move down the track, and the cell divides.” The audience watches the wiggling cell split and move apart.
Murray’s spindle checkpoint is a gene with a dual job. Not only does it make the cell wait for the chromosomes’ centromeres to line up properly before activating the scissors. It also helps realign chromosomes when necessary. These two critical tasks help diminish the potentially fatal mistake of a cell division in which the new cells will end up with either too many or too few chromosomes.
Age, Down syndrome, and a continuing saga
As promised, Murray summarizes his quest to understand a thorny genetic problem: Why does the incidence of Down syndrome increase with the mother’s age?
After examining various theories and discarding them, scientists now believe that the spindle checkpoint’s efficacy may diminish with age. “This is an especially compelling theory since the spindle checkpoint has two jobs,” Murray says. “If it fails at one, it’s easy to see how something could go wrong.”
Murray glances at the clock. He’s been talking fast, for an hour, and it seems the final science research lecture for this academic year must come to a close. Before he ends, Murray notes that in five to 10 years, “we should have an explanation, if not a fix, for the increasing incidence of Down syndrome with mother’s age.” An observer can imagine Murray rushing back to his lab, though it’s late. His absorbing research will continue. And perhaps, by next year at this time, he may have helped decipher yet another of the cell’s mysterious mechanisms in the continuing saga of the chromosome chronicles.