From the Special Topic of
In our Special Topics analysis of Tuberculosis
(TB) research over the past decade, the work of Dr. Roland
Brosch ranks at #4 by total cites and #2 by cites/paper,
based on 23 papers cited a total of 3,931 times. He is also
a coauthor on the papers ranked at #1 and #11 on the list
of the most-cited papers from the past 10
His record in
Essential Science IndicatorsSM from
includes 36 papers, the majority of which are classified in the field of
Microbiology, cited a total of 4,670 times between January 1, 1998 and
December 31, 2008. Dr. Brosch the Head of the Integrated Mycobacterial
Pathogenomics Unit at the Institut Pasteur in Paris, France..
In the interview below, he
about his work related to TB.
Would you tell us a bit about your
educational background and research experiences?
I did my studies in biology at the Universities of Graz and Salzburg
in Austria and received a Ph.D. from the University of Salzburg. As part of
my postdoctoral work, I studied the genomic and phenotypic diversity of the
food-borne pathogen Listeria monocytogenes at the Institut Pasteur
in Paris, France, and the University of Wisconsin, Madison, USA, before I
became interested in Mycobacterium tuberculosis and joined the
group of Professor Stewart Cole, who was leading an M.
tuberculosis genome-sequencing project at the Institut Pasteur in
collaboration with the Sanger Institute (Hinxton, UK) in order to decipher
the genetic bases of this major human pathogen.
It was an extraordinary experience, scientifically and socially, to be part
of the team who got the first broad insights into the gene content of this
key pathogen. In the following 10 years I had the great opportunity to
continue working in the lab of Stewart Cole. I used comparative genomics of
M. tuberculosis and Bacille Calmette-Guérin
(BCG), the attenuated vaccine strain, and undertook functional
analyses to extract the biological and evolutionary information contained
in the genome data.
Recently, Stewart took on a new position at the EPFL in Switzerland. In
2008 I became head of the new research Unit at the Pasteur Institut that is
dedicated to integrated mycobacterial pathogenomics. In addition, several
other units on the Pasteur campus are working on various other aspects of
tuberculosis research, such as genetics, structural biology, immunology,
histo-pathology, and host-susceptibility, which makes the Institut Pasteur
a very stimulating place to do mycobacterial research.
What influenced your focus on
Tuberculosis has had a huge impact on human history, and continues to claim
millions of lives at the beginning of this 21st century. The emergence and
spread of multi- or extensively drug resistant (MDR, XDR) strains of M.
tuberculosis represent an additional threat. Thus, further research on
this pathogen and its interaction with the host is absolutely crucial to
cope with this problem in the future. Many novel tools of molecular biology
have been developed in recent years and their adaptation to mycobacteria
open new exiting insights into the biological properties of M.
The majority of your papers in our analysis deal
with research into the Mycobacterium tuberculosis genome.
What important discoveries have been made about this genome, and how
has this knowledge helped with the disease?
The genome of M. tuberculosis contains all the information this
organism needs to persist and multiply in the host. The genome information
together with functional genomics studies now allow us to determine the
weak points in the metabolism of the bacterium, which is, for example,
important for the development of novel anti-tuberculosis drugs.
Your most-cited paper in our analysis is the 1998
Nature paper, "Deciphering the biology of Mycobacterium
tuberculosis from the complete genome sequence," which has been
cited close to 3,000 times. Would you walk our readers through this
paper and why you think it is so highly cited?
This landmark paper has indeed changed the way in which scientists
look at M. tuberculosis. The genome of M. tuberculosis
contains large regions of particularly high GC content and repeated motifs
that have posed an enormous challenge for the finishing phase of the
sequencing project. It was the use of large insert size clone libraries,
which finally enabled us to bridge the gaps in the shotgun libraries and to
establish a reliable genome sequence.
"Tuberculosis has had a huge impact
on human history, and continues to claim
millions of lives at the beginning of this
The next major challenge was the annotation and interpretation of this raw
sequence. About 4,000 genes have been identified in the genome of M.
tuberculosis including several from new gene families, many of which
are now the subject of intense and focused research. The availability of
this information has enabled a variety of novel approaches that include
studies of the transcriptome, the proteome, protein structures, and/or
The information content of the genome sequence of M. tuberculosis
benefits many different disciplines of mycobacterial research, and that is
why the paper is so highly cited. Indeed, biological and medical research
without access to genomic data is difficult to imagine nowadays.
Another paper you coauthored that is receiving
citation attention is the 1999 Tubercle and Lung Diseases
paper, "Analysis of the proteome of Mycobacterium tuberculosis in
silico." Please tell our readers about this paper and its
This paper published in Tubercle and Lung Diseases (now
named Tuberculosis) contains an extensive bioinformatic analysis
of the M. tuberculosis genome, which identified large gene
families that seem to play important roles for the bacterium. Some of these
families, such as the ESAT-6 family or the MmpL family, have since then
been shown to be essential for the pathogenicity of the organism.
In 2008, you coauthored a paper in Genome
Research, "Insights from the complete genome sequence of
Mycobacterium marinum on the evolution of Mycobacterium
tuberculosis." Would you talk a little bit about this
paper—its goals, findings, and implications for the
The results presented in this paper are based on the collaborative
work of groups from several institutions. This work nicely demonstrates
that during the early evolution of M. tuberculosis, both genome
downsizing and gene acquisition via horizontal gene transfer seem to have
played major roles for M. tuberculosis becoming a pathogen.
What are your hopes for progress in TB research
over the next decade?
My hopes for the TB research of the next decade are focused on the
functional analyses of the genes that have been identified to be involved
in the pathogenicity of M. tuberculosis. Knowledge of how M.
tuberculosis uses these genes during the infection process is
important to find new ways to target this major pathogen. In addition, due
to more and more genome sequence information becoming available,
information on the origin, evolution, and specific adaptation of M.
tuberculosis to its host should help to find factors that are crucial
for M. tuberculosis being such a successful pathogen.
What would you like the "take-away lesson" about
your research to be?
I think that the research to which I have contributed within the last 10
years has allowed important new insights into the biology and evolution of
M. tuberculosis and closely related members of the M.
tuberculosis complex. This knowledge will be exploited within the next
years for novel prophylactic and/or therapeutic
Dr. Roland Brosch
Integrated Mycobacterial Pathogenomics
KEYWORDS: TUBERCULOSIS, TB, MYCOBACTERIUM TUBERCULOSIS,
COMPLETE GENOME SEQUENCE, VACCINE, MULTI-DRUG RESISTANCE, EXTENSIVELY
DRUG RESISTANT, GENE FAMILIES, GENOMICS, PATHOGENICITY.