A recent analysis of Essential Science
Reuters, hailed Professor Stephen Neidle
as a New Entrant to the top 1% of
scientists in the field of Biology &
Biochemistry. His current record in this field
includes 33 papers cited 1,189 times between January
1, 1998 and October 31, 2008. He also has 56 papers
cited a total of 1,564 times over the same period in
the field of Chemistry.
Professor Neidle is the Director of The Cancer
Research UK Biomolecular Structure Group and Professor
of Chemical Biology at the University of London's
School of Pharmacy.
This month, ScienceWatch.com
talks with Professor Neidle about his highly cited
Would you tell us a bit about your educational
background and research experiences?
I was originally educated as a chemist and crystallographer at Imperial
College London, working on natural products and antibiotics. I subsequently
moved into more biological areas, firstly in the Department of Biophysics
at King's College London, and then for 17 years at the Institute of Cancer
Research, a world-renowned center for both fundamental and translational
studies in cancer science.
"It is our hope that our knowledge
of telomeric quadruplexes will be useful in
the development of novel against effective
against some of these
In 2002 I moved to the School of Pharmacy in Central London, to a new chair
of Chemical Biology. I have continued to retain my focus as a chemist,
which provides a unique perspective on molecular behavior in biological
systems and its exploitation for drug discovery.
What would you say is the main focus of your
The laboratory that I have built up over the years emphasizes an integrated
chemical and structural approach to the discovery of new therapeutic
agents, mostly in the cancer area. Much of our work over the past dozen
years has been on the discovery of novel agents targeting human telomeres
in cancer, and in particular we have been active in the study of
higher-order DNA structures known as quadruplexes.
Quadruplex-forming sequences occur within telomeric DNA and in promoter
regions of a number of oncogenes; we are involved in determining the
three-dimensional structures of these quadruplexes, designing and
synthesizing selective small molecules that will bind to them, and in
evaluating the biological consequences in a range of cancer cell types.
Several of your papers deal with telomeric DNA. What
makes telomeric DNA such a topic of interest?
Telomeric DNA is a fundamental feature of all eukaryotic chromosomes. For
those of us in the cancer area, the story started with the discovery in the
mid 1990s that telomeric DNA is maintained in the overwhelming majority of
cancer cells by the action of the telomerase enzyme complex, which
synthesizes telomeric DNA repeats and essentially maintains the
immortalization of cancer cells. By contrast, in normal somatic cells,
telomerase is not significantly expressed and the normal mechanism of DNA
replication results in progressive shortening of telomeric DNA so that
after a number of generations normal cells are no longer viable. So this
knowledge developed into the concept of targeting telomerase and its
substrate telomeric DNA as a therapeutic strategy.
Your most-cited paper is the 2002 Nature
article, "Crystal structure of parallel quadruplexes from human
telomeric DNA," (Parkinson GN, Lee MPH, Neidle S, 417: 876-80,
20 June 2002). Would you talk about this paper, its goals, findings,
and significance for the field?
This paper is the first atomic-level description of the structure formed by
folding human telomeric DNA, crystallized in near-physiological conditions.
That itself continues to be of interest and is used as a template for the
discovery of novel small molecules as Telomere Targeting Agents. The
structure, though, is remarkable—it shows the quadruplex as a
propeller-like arrangement and this was totally unexpected and novel. It
has subsequently catalyzed a great deal of interest and activity (and
controversy!). This quadruplex fold is turning out to be a paradigm for
many other quadruplex structures, and is present in the majority of the
promoter quadruplexes studied more recently.
What sort of controversy did this work
"Telomeric DNA is a fundamental
feature of all eukaryotic
Crystallographic studies can provide a uniquely detailed view of the
three-dimensional structures of biological molecules, although they are
sometimes criticized as not representing structures in solution. NMR
studies of human telomeric quadruplexes (in dilute solution) have revealed
some arrangements that are distinct from the structure that we observed.
However, it is now apparent that these molecules can adopt a range of
structures, dependent on even small changes in environmental conditions,
and that the topology of these quadruplexes in more concentrated solution,
closer to physiological conditions, corresponds to that observed in the
crystalline state (which is actually heavily hydrated).
What are the hoped-for applications in telomeric DNA
Firstly, increased knowledge of telomere organization and function.
Secondly, as I have described, new therapeutic agents for human cancers.
What would you like to convey to the general public
about your work?
We are getting much better at treating many forms of human cancers, but
progress with some of the commonest (e.g. lung and pancreatic cancers,
melanoma), is still slow. It is our hope that our knowledge of telomeric
quadruplexes will be useful in the development of novel against effective
against some of these cancers.
Professor Stephen Neidle
CRUK Biomolecular Structure Group
The School of Pharmacy, University of London