In a recent analysis for ScienceWatch.com,
Dr. Jim Woodgett was named a
Rising Star in the field of Molecular Biology &
Genetics. His current record for this field in
Essential Science Indicators from
Reuters includes 23 papers cited a total of 2,061
times between January 1, 1998 and June 30, 2008. His
full record for this period, over all fields, includes
72 papers cited a total of 5,122 times.
Dr. Woodgett is the Director of
Research at the Samuel Lunenfeld Research Institute of Mount
Sinai Hospital in Toronto, Ontario, Canada. In the interview
below, he talks with us about his highly cited
Please tell us a little about your research and
I've always been interested in signaling pathways and their role in various
diseases, particularly cancer and diabetes. I'm from the UK originally and
trained and worked with several great signal transduction scientists
Philip Cohen (Ph.D., Dundee),
(see also ¦
see also (postdoc, Salk Institute), and Mike
Waterfield (first independent position, London).
I've been in Toronto for over 15 years, first at the Ontario Cancer
Institute and for the past three years at the Lunenfeld, which, with
brilliant people like Tony Pawson, Jeff Wrana, and Frank Sicheri, as well
as young stars like Dan Durocher, Helen McNeill, and Anne-Claude Gingras,
is a scientific mecca for signal transduction. It's a small institute (32
investigators) but incredibly interactive, hence I've benefited greatly by
collaborating with scientists like Andras Nagy, Dan Drucker, and Jim Dennis
in rapidly developing new ideas.
What do you consider the main focus of your research,
and what drew your interest to this particular area?
"I think this is why many promising
drugs still fail—we overlook
cell-specific and temporally distinct
functions associated with a given
Everyone in the lab works on some aspect of signaling in disease with
breast cancer, and
stem-cell fate determination being our core
interests. We tend to focus on protein-serine kinases since these seem
to be the command and control points in cells, and it's gratifying to
see how many have become important therapeutic targets. Despite the
focus on protein kinases, most of our work depends on cell biology and
mouse genetics (our single largest research expense).
Your most-cited paper in our database's field of
Molecular Biology & Genetics (Hoeflich KP, et al.,
"Requirement for glycogen synthase kinase-3 beta in cell survival and
NF-kappa B activation," Nature 406: 86-90, 6 July
2000), as well as many of your other highly cited papers, deal with
glycogen synthase kinase-3. Would you talk a little bit about this
aspect of your research?
It's somewhat scary, but this protein kinase figured prominently in my
Ph.D. thesis. I've known it longer than my wife! You might think spending
27 years on a single enzyme is excessive or, perhaps, obsessive, but this
kinase throws out surprises all the time. It was first identified by Phil
Cohen's group as a key regulator of glycogen synthase, the rate-limiting
enzyme of glycogen synthesis. I cloned the GSK-3 genes in 1990 and within
two weeks of that publication two other papers appeared from fly
geneticists who'd cloned a key gene involved in developmental patterning.
The sequence showed their gene was GSK-3. That was our first clue that
there was more to this kinase than sugar metabolism. Since then, it's been
a case of one unexpected finding leading to the next. That said, this
kinase sits downstream of five major signaling systems and targets over 50
regulatory proteins including proto-oncogenes and a slew of transcription
factors. It is clearly "well connected."
The two genes that encode this kinase overlap in many functions so our most
recent work has focused on understanding the tissue-specific and
isoform-specific functions. We've also found some remarkable biological
effects when both genes are inactivated in particular cell types, so this
kinase has a few more surprises up its sleeve. What's perhaps most
interesting from a disease standpoint is that different levels of GSK-3
activity are associated with quite different phenotypes and disorders. This
has therapeutic implications as well as insights into how cells partition
and specialize their rather generic signaling pathways.
Several of your highly cited papers deal with
stress-activated protein kinase pathways. What is the importance of
Good question, because we still don't fully appreciate the answer! The body
of work on stress-activated protein kinases (now better known as JNKs) was
a result of a long and productive collaboration with Joe Avruch and John
Kyriakis in Boston. We naively thought the SAPK/JNK pathway would mediate
the appropriate transcriptional response to stress-inducing stimuli such as
apoptosis or growth arrest since the primary target of these kinases was
However, in subsequent work from many labs, it has become clear that the
pathway rarely, if ever, works alone and the consequences of its activation
are largely dependent on context. Dissecting the specific physiological
functions has been complicated by the fact that the agonists of this
pathway induce many other systems. We think we have a handle on this at
long last via generation of a constitutively active mutant, which I hope
will allow us to isolate the specific functions of the SAPK/JNKs.
How has this field changed since you first started
working in it?
"You might think spending 27 years
on a single enzyme is excessive or, perhaps,
obsessive, but this kinase throws out
surprises all the time."
Perhaps its a sign I've been working on the same pathways for too long but
there have been dramatic changes over the past 20 years in signal
transduction, enabled partly through technological development
(tissue-specific gene inactivation, live cell microscopy, and proteomics
are a few) but also by the realization that signaling is dynamic and
contextual. It's not enough to understand which protein binds to another;
you need to know where in the cell, when in the response, and how the cell
adapts to the change through feedback systems. I think this is why many
promising drugs still fail—we overlook cell-specific and temporally
distinct functions associated with a given target.
We're getting better but still have a long way to go in explaining the
behavior of these hyper-interactive and inter-dependent pathways. The
amazing degrees of stability, consistency of response, and adaptivity
inherent in biological systems should play a bigger role in our models to
explain how these control circuits work in a reliable manner.
Where do you see this work going in five to ten
As we become more sophisticated in experimentation, I think we'll be able
to more accurately predict and then mimic the properties of signaling
pathways. This should lead to greater chances of success in drug
development leading to an effective product without significant side
effects. As we understand how these systems talk to each other, we'll be
better able to sculpt appropriate treatment regimens, analogous to
conformal radiation therapy. Right now, we stick a Hoover Dam in the middle
of a surging pathway rather than modulate the tributaries.
I also think that a major benefit of the resequencing projects will be
provision of more information about the combinatorial effects of many small
differences, leading to interventions tailored to the individual. Since
signaling pathways are the conduits of cellular functions, focusing on
polymorphisms of the molecules that comprise these systems should provide a
practical roadmap for personalized medicine.
Dr. Jim Woodgett
Samuel Lunenfeld Research Institute
Joseph and Wolf Lebovic Health Complex
Mount Sinai Hospital
Toronto, Ontario, Canada
Coffer PJ, Jin J, Woodgett JR, "Protein kinase B (C-AKT): A
multifunctional mediator of phosphatidylinositol 3 kinase
activation," Biochem. J. 335: 1-13, Part 1, 1
October 1998. Source:
Essential Science Indicators from
Keywords: signaling pathways, signal transduction, type-2
diabetes, glycogen synthase kinase-3, NF-kappa B, stress-activated
protein kinase, SAPK, JNK.