Dormant bacteria

Tuesday, July 29th, 2008 by hinrich

Mycobacterium tuberculosis is the bacterium causing tuberculosis. While there are a number of antibiotics that can kill the bacterium, most of these antibiotics will not kill dormant bacteria. Dormancy is the technical term that refers to a state in which the bacterium does not actively divide. It is the state that the bacterium typically goes into after the initial infection, leading to a latent infection without any obvious harm. Why is this a problem? Because it is estimated that approximately one-third of the world population carry the bacterium. And even if these people do not suffer from tuberculosis, in situations when the immune system is weakened, the bacterium can come out of this state, start multiplying ("replicating") and consequently cause the illness.

In 2005 we published an article about a new compound that we had identified (a so-called diarylquinoline) which promises to be very active in killing mycobacteria. This compound is also referred to as R207910 (this is the internal number given here at Janssen Pharmaceutica where the molecule was originally synthesized and where the anti-mycobacterial characteristics were discovered) or TMC207 (the internal number given to the compound by Tibotec who has taken over the compound to develop it further).

We have now published an article with the title "Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis" in the Journal of Biological Chemistry. In essence, we show data that suggests that dormant bacteria still require the fully functional enzyme ATP synthase to continue to provide it with energy (ATP) even though it needs only very little in this resting state. When using our compound to block the enzyme, the energy available to the bacterium drops even further. This reduction in available energy seems to be sufficient to actually kill the dormant bacteria.

Having bactericidal activity on both actively replicating bacteria and on dormant bacteria makes R207910/TMC207 especially promising and underlines the potential of the ATP synthase as a target in fighting tuberculosis. You can read the abstract of the paper here. A review of our new compound and it's mechanism of action can be found in this Science Enhanced Perspectives article (free access).

Posted in Tuberculosis

Differential variability

Thursday, July 03th, 2008 by hinrich

Differential Variability

A recent article by Ho et al. in Bioinformatics introduces a concept that is novel to the analysis of gene expression microarray data: differential variability. In essence, until now data analysts typically looked for differences between two groups (e.g. normal individuals vs. patients with a certain disease) by searching for differences between the average signal intensity of each group. The result would be a gene, which - on average - is more active (i.e. has higher mRNA levels) in one group than in the other. The new concept now looks at differences in how variable the activity is in one group vs. another. While such an approach is tricky with very few samples, it could prove quite useful for examples with a sufficiently large number of individuals in each group. Furthermore, this approach is definately not limited to the field of gene expression but should be applicable for all areas of molecular profiling (e.g. proteomics, metabolimics, microRNA, etc.).

The article can be found here.

Posted in Molecular Profiling

Success in science

Tuesday, July 01th, 2008 by hinrich

A key element of molecular biology research is that we do experiments to test hypotheses and to make (unexpected?) discoveries. But I also believe, that scientists always need a bit of luck to find something. No matter how good a scientist is, there always seems to be a bit of luck needed. So, what makes a scientist continously successful (= making more than one discovery every five years)? I think, that one has to be as careful as possible with the planning, conducting and the analysis of experiments, so that if an experiment would contain data that revealed a new scientific discovery, the experiment was done careful enough to actually pick it up.

...and documented well enough to be repeatable...

Posted in Science