Perutz prizewinning essayist Collette Tourlamain introduces the fatal Pap.
Meet Pap. He is a virus (human papillomavirus type 16 to give him his full name), a small circle of DNA with a protein coat. He is at the start of his adult life, about to infect a new person. She is having sex with her boyfriend. She does not know this will cause her death. She has a slight scratch on her cervix, allowing Pap to infect the cells at the base of her protective cervical lining - the epithelium.
Pap has found his new home. He takes off his protein coat and makes about 50 copies of his DNA and also his armoury of functional proteins. In this type of cell it is easy: the basal cell is actively dividing, replicating its DNA, so there is plenty of replication machinery for him to use.
Later, in the higher levels of the epithelium, it will become harder for him to make the thousands of copies of his DNA that will ensure the continuation of his genes. As the cell divides, Pap uses his E2 protein to cling tightly to the cellular chromosomes so that he stays in the new cells. He will be able to rise up the epithelium as the cells differentiate (by ceasing replication and gaining more protective functions) and he will also be able to create the outer protein coats of his offspring.
Unfortunately for Pap, although the differentiated cells provide him with everything necessary for the maturation of his offspring (which is not possible in dividing cells), they make it very difficult for him to replicate his DNA. They do not replicate themselves, so do not make the right machinery. Pap, a cunning virus, has found a way round this. Using his E7 protein, he induces the cell to make replication machinery. This means his DNA can be copied 10,000 times in a single cell. He stops the cell from dying (a response to abnormal activity of the replication machinery) by using his anti-lethal weapon E6. The hard part is over. He just needs to reach the top of the epithelium, make protein coats and his offspring can be released in exfoliated dead cells, ready to infect another cell.
But there is a problem. For some reason, the cells start to replicate their DNA with the newly activated machinery and divide again. Pap and his copies are trapped in the cells for many years. The cells divide many times in an increasingly uncontrolled manner. They give up their protective functions and eventually start outgrowing their epithelial home, passing into other organs in the body.
The woman, 15 years older and married with two children, is very ill. She has cervical cancer, too far advanced for treatment, and is slowly losing the battle to control the rebel cancer cells that once formed the viral home and are now taking over her body.
Cervical cancer is the second biggest killer of women worldwide. It is caused by high-risk genital human papillomaviruses. The viral proteins E6 and E7 knock out key cellular controls of DNA replication and cell death. Investigation into the actions of E6 and E7 has helped explain the normal mechanisms that control these functions, advancing research into all types of cancer. Most of the work has focused on interactions of E6 with p53, a protein that induces potentially cancerous cells to die, and E7 with Rb, a protein that controls the replication of all cells. These proteins are abnormal in nearly all cancers.
It has emerged that E6 is able to interact with a number of other cellular proteins. This also seems to be a factor when normal cells become cancer cells. One of the proteins that interacts with E6 is Mcm7. Mcm7 is essential for cellular DNA replication and is tightly regulated to ensure that the cell replicates its DNA only once each time it divides, another control against cancer. I want to know whether the interaction of E6 with Mcm7 subverts this control.
To find out, I am using a cell-free DNA replication system. I take nuclei from cells that are not replicating and induce normal DNA replication by adding cytoplasm from cells that are actively replicating. By adding E6 to the system, I can see whether it alters the way in which the nuclei replicate their DNA. This will suggest whether the interaction of E6 with Mcm7 contributes to the cancer caused by the virus. If so, it is likely that these control mechanisms also break down in other cancers. I hope my work will provide clues about the common mechanisms for the breakdown of DNA replication control in cancer. Who knows, perhaps Pap will help us cure cancer as well as causing it.
Collette Tourlamain is a Medical Research Council research student, based in the department of pathology at Cambridge University. This essay won first prize in the Max Perutz essay prize, awarded by the MRC and backed by The THES .