A cancer cell undergoing apoptosis

courtesy of University College Dublin

Seamus Martin's apoptosis research group at Trinity College Dublin is small - no more than eight or ten researchers, most of them PhD students - yet it punches well above its weight, at home and abroad.

In 2002, four years after starting his group, Martin was fourth in the world apoptosis citation rankings. Now, as Smurfit Professor of Medical Genetics at the Trinity, he reckons they are also Ireland's most cited life-sciences research team, with more than 13,000 citations for 80 apoptosis papers, according to citation tracker ISI. Their latest findings look to be continuing the trend, opening a new line of apoptosis research, and possibly shedding light on how the process evolved.

Martin was drawn to apoptosis while a PhD student 20 years ago, attracted by the essential nature of the process for healthy development of organs and tissues. "Every cell that divides has to get permission, and likewise cell death. It is highly regulated, with a kind of yin-yang balance."

The ramifications of dysregulation were also compelling, he says. "Apoptosis is central to many diseases. And if we knew how to control it, how to kill cells, then that would be really useful, especially in treating cancers."

Yet Martin is not motivated by the search for a cancer cure. Instead, he is driven by the challenge of understanding the fiendishly complex mechanisms behind apoptosis: seeking to identify the many proteins that monitor a cell's status, make life-or-death decisions, and clean up afterwards. "We identify new genes and clone them, express the protein, study its mechanism, structure, and cellular function, and increasingly now, look at its function in vivo in animals."

Significantly, his group has identified a new and unexpected role for the Bcl-2 family of proteins, some members of which activate apoptosis, and others oppose it. In 2006, Martin found that some Bcl-2 proteins are also involved in mitochondrial morphogenesis, the process of fusing and fragmenting the organelles (Molec Cell, 21:761-73, 2006). The work could shed light on how the cell death machinery evolved and might explain anomalies, such as the fact that in Caenorhabditis elegans, some Bcl-2-like proteins reside on the mitochondrial membrane.

Mitochondria had previously been implicated in apoptosis, but mitochondrial morphogenesis in the absence of apoptosis was a new observation. Martin believes that the Bcl-2 role in mitochondrial dynamics is more ancient than, and distinct from, its role in cell death control.

Richard Youle, chief of the Biochemistry Section at the US National Institute of Neurological Disorders and Stroke (NINDS), and an original proponent of the idea that mitochondrial breakup might drive apoptosis, agrees. "There is evidence that Bcl-2 family members regulate both apoptosis and mitochondrial morphogenesis and that these two activities are not necessarily linked. For example, Martin has shown that Ced-9 [the nematode version of Bcl-2] expressed in mammalian cells induces mitochondrial fusion without altering apoptosis." The two roles, Youle says, might reflect an as yet undiscovered and presumably more fundamental Bcl-2 activity.

Drug firms already have Bcl-2 modulators in trials as cancer drugs. Martin's findings suggest that a cancer drug that targets Bcl-2 proteins could also affect mitochondrial function. His five-year plan is to tease this out, focusing on a Bcl-2 subgroup, the BH3-only proteins, which activate cell death and attack mitochondria. Even if anticancer drugs did disrupt mitochondrial function, Martin's guess is that this is unlikely to be a major problem, given that chemotherapy drugs are generally used only in acute short-term doses.

Martin's research has received funds from Science Foundation Ireland, the Health Research Board, and the Wellcome Trust, but he says funding isn't the key to success. It's about "passion, good ideas - ours is an hypothesis-driven field - and having excellent people," he says. "If you have excellent people, you can do good research, but if you don't, then all the money in the world is of no use."