This author interview is by Dr Alan Tartakoff, of Case Western Reserve University.  Dr Tartakoff's full paper, The Axis of Progression of Disease, is available for download in Cancer Informatics.

Please summarise for readers the content of your article.

We describe fundamental concerns that plague the analysis of disease.  The most crucial is the realization that outcomes of single genetic or environmental changes often are unpredicatable - given the large number of molecular interactions that occur.   Moreover, the degree of unpredictability is likely to increase with time of progression - in other words, as a function of the cumulative set of secondary and tertiary changes.  From this chronological perspective, it becomes evident that possible targets for intervention are those that lie at early points.  This is both because such targets should be easier to predict and because at early times fewer far-removed changes will have occurred.  This realization is sobering in the context of diseases of unknown or multiple causation.  If distinct initiating circumstances do lead to overlapping molecular phenotypes, those potential targets are likely to lie far downstream, i.e. after irreversible changes have occurred.  We therefore describe strategies that might be used to identify early changes.

As a fascinating example of the prevalence of secondary, seemingly-unrelated changes, studies of cells that carry single well-defined mutations show that they often acquire multiple secondary mutations.

How did you come to be involved in your area of study?

My fascination with chronology started with an interest in Huntington's Disease.  Although only a single gene is mutated, studies of Huntington's have led to the realization that even a single genetically well-defined mutation can have multiple unmanageable molecular consequences.   Huntington's investigators have concluded that major damage is characteristic of mitochondria, membrane traffic, and the mitotic spindle.  Durer had to deal with some of the same varied testimony in making his famous drawing of an elephant.

What was previously known about the topic of your article?

A great deal was known about genetic lesions and the ultimate deadly consequences to which they lead, both for cancer and for other diseases.  Nevertheless, causal connections have often been unclear and targets for possible molecular intervention have been difficult to identify.   The bioinformatic studies of my co-author (Di Wu) exemplify approaches that can be used to analyze such complexity.

How has your work in this area advanced understanding of the topic?

I hope that our insistence on the chronology of change will be beneficial to others.  Certainly, Di Wu's algorithms and correlative studies of large data sets will be helpful.

What do you regard as being the most important aspect of the results reported in the article?

The realization that we need to take into consideration the sequence of metabolic, biochemical and genetic changes that occur.  Focus on a single time-point will often not be sufficient.

Dr Tartakoff's Institution Profile

share on