A chance discovery of recurring, mildly-low blood platelets in a local family has led Drs Ian Morison and Liz Ledgerwood on a fascinating international collaborative journey to understand a fundamental cellular process that contributes to many major diseases.

Both senior research fellows in the Department of Biochemistry, Morison and Ledgerwood's findings were published this year in the journal, Nature Genetics. However, the journey started more than 10 years ago, with one family member whose surgery was cancelled due to mildly-low platelets, the cells in the blood that stop bleeding.

"Some blood tests later, we knew we had found a condition that had never before been described," says Morison. This was enough to trigger his curiosity, and he and his team began their search for the gene responsible.

"It was one of those amazing needle-in-a-haystack stories, to find a single letter, among three billion letters of DNA within the genome, that was shared by this family, but not by others," Morison says.

Fortunately for the researchers, a family genealogist had already tracked the family tree back to 1831 and beyond - to a time when their ancestors were mining tin in Cornwall.

"It was one of those amazing needlein- a-haystack stories, to find a single letter, among three billion letters of DNA within the genome, that was shared by this family, but not by others."

They were able to trace each branch of the family and eventually gathered blood samples from 80 family members, finding about 30 with low platelets. Those samples helped them begin their search for the elusive letter and, after three years, they had narrowed it down to a small section of the genome with only one million letters.

When they eventually found the change unique to the family, it provided quite a surprise. The gene in question affected a protein called cytochrome c, a wellknown protein that is an essential part of a cell's energy production.

This was the first discovery of a mutation in cytochrome c and, even more surprising, the mutation affected part of the protein that has remained exactly the same for two billion years across a broad range of living organisms, from yeast to the grey whale.

Studies in Ledgerwood's laboratory have shown that the mutation does not affect energy production. Instead, it affects a second, recently-discovered role of cytochrome c - the control of programmed cell death, or "cell suicide", a natural process necessary for maintaining the correct number of cells in the body. Remarkably, the mutation makes cytochrome c better at triggering cell death.

Work by platelet expert Professor Elisabeth Cramer-Bordé, from the Institut Cochin in Paris, has uncovered just why these family members have low platelets. Platelets are made in the bone marrow from megakaryocytes, in a very specialised form of cell death. In these family members this process is highly abnormal, with the megakaryocytes dying early and releasing their platelets into the bone marrow space, instead of into the circulation.

Ledgerwood says conventional wisdom suggests affected family members would be ill and suffer from brain disease. However, apart from their low platelets, these family members are healthy and long-lived.

"Answering this paradox will provide significant insights into a critically important normal cellular process," she says.

"Correctly-controlled cell death is vital. In cancer, cells don't die when they should, while in brain diseases like Alzheimer's they die prematurely."

With their recent success in obtaining a grant from the Marsden Fund, the team has some exciting work ahead. "We hope that by unraveling the fine details of where, when and how the mutated cytochrome c is better at promoting cell death, we will discover new ways to modify the death process. This may help treat diseases that involve abnormal cell death in the future."

Funding