The winner of the Merville Lay Seminars at UCD is trying to prevent the kidney damage caused by some cancer therapies. Dick Ahlstrom reports
Kidney damage is a major problem for many people undergoing chemotherapy treatments for cancer. The research student who last week won the annual Merville Lay Seminars competition hopes to find a way around this problem.
Each year, six finalists from University College Dublin's departments of pharmacology and biochemistry battle it out in front of a lay audience. Their goal is to explain their research in language that anyone could understand, and a lay judging panel, which this year included rugby international, Denis Hickey, chooses the winner.
The laurels this time went to pharmacology for a presentation made by Seema-Maria Nathwani, a researcher in the third year of her four-year PhD research programme. The title of her paper, "Cancer and Drug Treatment: Kidney Cells Caught in the Crossfire", describes her work very clearly. She studies the biochemical processes involved in kidney cell death after exposure to the anti-cancer drug, cisplatin.
The drug is very effective at killing cancer cells, but during treatment it tends to build up in the kidneys. They are exposed to high levels of cisplatin as they attempt to clear it from the blood and before it can be excreted.
Working under the direction of Prof Michael Ryan, she has received funding from Enterprise Ireland and from UCD.
"People can only be given low doses of the drug because of its toxicity," she says. Her goal is to block the process of cell death, apoptosis, which is triggered by the build-up of cisplatin.
Apoptosis is a highly regulated process involving a cascade of proteins that work in concert to eliminate the cell. It is also a complex process, making it a challenge to follow as the cell breaks down. After examining several pathways, she began looking more closely at one that involves a protein called p53. She noted that cells challenged by cisplatin often displayed elevated levels of p53 before going into apoptosis.
"P53 is the tumour suppressor gene and is frequently referred to as the guardian of the genome because it is the switch between life and death," Nathwani explains. The p53 protein is missing in about half of all cancer types, allowing these cells to survive, and is too plentiful in the kidney cells that die because of cisplatin. "I went on to see what was causing this," she adds.
She found no increase in either RNA - the genetic code that produces the protein - or increased transcription, the cellular process that allows RNA to make protein. "That ruled out the death being caused by overproduction of p53," she explains. "Now I think it is due to some insufficient breakdown of the protein."
Her research involves looking closely at two proteins that control the balance of p53 inside the cell, ubiquitin and sumo. Usually the interaction between ubiquitin and sumo keeps the balance of p53 correct for cell survival,Nathwani says. When ubiquitin attaches to p53 the protein can be destroyed. When sumo attaches, the p53 can survive and persist in the cell. She now believes that exposure to cisplatin causes something to go wrong, allowing sumo to gain the advantage and p53 to build up in the cell causing death.
If this proves correct then it opens up new opportunities for drugs that can protect kidney cells against damage. It is now possible to produce custom-made "designer drugs" that attach to specific proteins, she explains. These could be used to target sumo and block its interaction with p53. The designers could also ensure the drug only targets kidney cells, so preventing apoptosis.
Second place in the Merville competition was won by William McCormack of biochemistry for his paper on controlling new blood vessel formation. Louise Glover of pharmacology took third place for her paper on malignant hyperthermia, an inherited muscle disorder.