Thursday, September 17, 2009

Pathways to Disease

Most common diseases, including the big killers like heart disease, are "complex": they can't be blamed on single causes like a particular gene. Instead, they result from a complicated interaction of factors that may include lifestyle, environmental exposures, or infection, as well as genetic effects. Moreover, large-scale surveys of genetic influences have confirmed that, in many cases, lots of different genes contribute to disease, each in a small way.

These generalizations also apply to cancer. Cancer differs from the other diseases because most of the genetic changes in cancer cells aren't present in the rest of the patient's cells. Instead, mutations, copy number variations, and large-scale chromosome anomalies accumulate as the disease progresses. These alterations are often abetted by early disruptions of the usual mechanisms for maintaining genome quality during cell division and for executing damaged cells. In spite of these differences, the first major results last fall from The Cancer Genome Atlas comparing the genetics of glioblastomas (deadly and virtually untreatable brain cancers) found no specific mutation was present in all of the tumors. The huge team of researchers did a comprehensive analysis including gene expression, copy number changes and epigenetic changes. But although some changes happened rather frequently, there was no single "smoking gun."

Nonetheless, these studies, in both cancer and other diseases, find clear patterns among the genes whose activity is altered in one way or another. When researchers put the changes in the context of the complex network of molecular interactions in the cell, most of the changes cluster along clear "pathways." As Todd Golub told a meeting I covered last year, just after the glioblastoma results were published: "What was gratifying about this was that this was not just a sprinkling of mutations randomly across the genome, which were difficult to decipher in the context of any kind of mechanistic understanding, but rather these were falling together in a set of pathways that were increasingly well understood in cancer."

I regard the word "pathway" is a bit of a misnomer, since it suggests a linear sequence in which each molecule affects the next one in a chain. In the early days, that was about all that experiments could get at, but researchers have long recognized that networks are messier than this. For example, there may be multiple, parallel influences of one molecule on another, and there are almost always feedback paths in which the final outcome comes back to modify the early steps.

Nonetheless, although they are complex and interconnected, these pathways give researchers a useful shorthand for navigating the rich networks of interactions and for communicating with others. In fact, many researchers specialize in particular pathways, getting to know each molecular member "personally," as well as the effects they have on one another.

Results like the glioblastoma study also show that the pathway level may be a more useful level of "granularity" for thinking about disease than the individual molecules are. Focusing on pathways (or "modules," or "motifs," or whatever) gives us simple-minded humans a better intuitive understanding of a disease, which is important. Moreover, in treatment, researchers can be led astray by focusing on molecular-level changes such as individual genetic variants, since these are not the same for everyone. Targeting specific pathways, for example with combination therapies that attack several "nodes" of the network at once, may prove to be more effective against diverse groups of patients.

But the most important benefit of isolating pathways may be that many of them are shared by different diseases, which is leading to new insights into the relationships between diseases.

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