Dormant bacteria II

Thursday, August 21th, 2008 by hinrich

Just a few days ago I have written about our recent publication showing a further reduction of available energy to dormant Mycobateria when treating them with TMC207/R207910. In the most recent edition of PNAS from August 19, another publication by Rao et al. underlines this finding.

The authors of the article have studied the mechanisms by which the bacterium provides itself with energy in the form of ATP. In one of their experiments they monitored the decrease in ATP as the concentration of oxygen was reduced in the environment. In the end, the authors saw 5-fold less ATP in hypoxic (little oxygen available) non-replicating Mycobacteria when compared to growing aerobic (normal oxygen levels) Mycobacteria. These smaller levels of ATP could be further reduced when the bacteria were exposed to increasing levels of TMC207/R207910. Rao et al. highlight that the production of new ATP is essential for the survival of the bacterium in this state. They show that TMC207/R207910 has bactericidal effects on such hypoxic non-replicating Mycobacterium tuberculosis cells.

Researchers currently favor the concept that the presence of the hypoxic non-replicating Mycobacterium tuberculosis bacteria are the reason why the treatment of patients is so lengthy. These bacteria are also viewed as causing the wide-spread latent infection with Mycobacterium tuberculosis. Therefore, if all clinical studies continue to be successful and no serious adverse effects were to be seen in patients, this compound clearly bears the potential to have a profound influence on treating tuberculosis.

You can read the abstract of the paper "The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis" by Rao et al. here.

Posted in Tuberculosis

Science in Pharma vs. Academia

Sunday, August 10th, 2008 by hinrich

Doing science in an academic institution has one major advantage: if one is successfully doing research, the results of the research represent the product of one's work (in the form of publications). These "products" in turn are used to build a scientific reputation and help when one applies for grants to pursue new scientific problems. Aside from many other attractive factors such as job security, another big plus is the relatively high level of freedom and independence.

So, why do I work for a pharmaceutical company? Well, yes, the paycheck tends to be bigger. But on the other hand, the scientific work is almost always the combined results of a large number of scientists and one's contribution tends be just a little piece in the big puzzle of coming up with a new medicine. Still, I find it highly satisfying to imagine that a scientific breakthrough here can potentially have a direct beneficial impact on the lives of many people. The feeling of having the power to contribute directly with my scientific work vs. hoping that my scientific results will get picked up by someone to turn this into something beneficial for society, is an important motivator for my research.

My blog posts in the category Tuberculosis refer to scientific developments about our promising new agent against Mycobacterium tuberculosis - the bacterium that is lethal to thousands of human beings every day. This is an example of what I have been referring to above. Even though I have been contributing only one scientific piece of the puzzle, the combined work of all scientists here at Johnson & Johnson who have been working on this project together with our academic collaborators has the potential to directly impact the lives of many patients.

Posted in Science

Genomic alterations in FFPE material

Tuesday, August 05th, 2008 by hinrich

Affymetrix has a microarray product (SNP arrays) that offers the potential to look at copy number alterations. While these alterations could most easily be studied in material coming from a fresh tumor biopsy, typically the tumor sample available to the scientist is only preserved material that is embedded in paraffin (FFPE). A disadvantage of this storage method (which is for practical reasons routinely done at hospitals) is the degradation of the DNA.

We have just published a study that looks at the quality of data one can obtain from such sub-optimally stored material. While we were able to optimize the laboratory procedures a bit and also identified critical steps in the preprocessing of the obtained data, the quality of this FFPE-material is still limited. Most striking to me were two observations:

  1. SNP probes seem to provide us with better results than CNV probes.
  2. The "wave pattern" that was proposed by Costantini et al. ("isochore" families) was clearly visible in our data. This pattern is caused by regions of high or low GC content along the chromosomes. One needs to correct for this pattern during the preprocessing of the data to avoid identifying GC-rich regions incorrectly as amplified or GC-poor regions as deleted.

You can read the abstract of our article ("Genome-wide copy number alterations detection in fresh frozen and matched FFPE samples using SNP 6.0 arrays") that is to appear in the journal "Genes, Chromosomes and Cancer" here.

Posted in Molecular Profiling