Interview Date: August 2009
From the Special Topic of
According to our Special Topics analysis of diabetes
research over the past decade, the work of Dr. Mark Cooper
ranks at #6 by total cites, based on 130 papers cited a
total of 6,085 times. In
Essential Science IndicatorsSM from
Reuters, Dr. Cooper's record includes 246 papers, the
majority of which are classified under Clinical Medicine,
cited a total of 7,787 times between January 1, 1999 and
April 30, 2009.
Dr. Cooper is the Director of the Danielle Alberti Memorial Centre for
Diabetes Complications as well as the Head of the Diabetes Division of the
Baker IDI Heart & Diabetes Institute in Australia.
In the interview below,
ScienceWatch.com correspondent Gary Taubes talks with Dr.
Cooper about his highly cited work.
Your most-cited paper is the 2001 New
England Journal of Medicine article on the "Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy" (Brenner BM, et al., 345: 861-9, 20 September
2001). How did this project come about and what was your role in the
I'm an endocrinologist by training, and I've been interested in diabetes
and kidney disease since the early 1980s. Then in the late 1980s, several
groups suggested that diabetic kidney disease was not only related to high
glucose, but also that there may actually be a hemodynamic pathway within
the kidney, the renin-angiotensin system, that is both activating kidney
injury and amplified by diabetes and high blood pressure. Over the next
five years, a range of new ways of interrupting that pathway became
available to clinicians.
In the early to mid-1990s, I became involved in experimental work looking
at what are called angiotensin-II receptor antagonists. The original
prototype was losartan, which was just being approved for use on high blood
pressure. It was considered particularly useful in diabetics. So we
launched a multinational trial to see if this drug could reduce the
progression of kidney disease, independent of its effect on blood pressure.
Brenner, the first author, was the chief investigator of this
What did the trial find and why do you think this
paper is so highly cited?
Mark Cooper with his team
Not only did losartan reduce the progression of kidney disease, but it also
reduced heart failure, so it is now considered the first line of therapy in
most international guidelines for people at risk of diabetic kidney
disease. That's why this paper has been so influential. At the time, by the
way, this was the largest-ever trial on people with diabetic kidney
Do you know what losartan does—what the
mechanism is—that leads to a reduction in two different diabetic
complications—heart failure and kidney disease?
Since this was a clinical trial, we can never say we know exactly what the
mechanism is. What we predicted is that by reducing the action of
angiotensin II, which is a profibrotic, proinfammatory molecule that
activates injury in end organs—the kidney, heart, and blood
vessels—we'd be attenuating that injury, which is accelerated in
diabetes. Many of my papers actually talk about this pathway and its
implications for diabetic complications, including kidney disease.
Your work spans a lot of different subdisciplines
in diabetes and kidney disease. Can you describe your thought process
in choosing journals for your publications?
It's become easier because of this world of impact factors. You work out
how good the paper is, and what the readership will be, and then decide
where to send it. If I have a paper that I think is very clinically
relevant, I'll start with the New England Journal of Medicine. If
I'm not successful, I'll go to The Lancet, then JAMA or
the BMJ. The reason we went to the BMJ first with my
second most-cited paper—the results from the CALM trial—is that
the BMJ has a tradition of publishing nephropathy papers. As
nephropathy is perceived as more and more important, more and more are
appearing in the New England Journal. But in 2000, the
BMJ seemed most appropriate.
In terms of the more research-oriented work, if I think it's an extremely
strong paper I might try the Journal of Clinical Investigations
first. If that doesn't work, and it's on the kidney, I'll probably go to
Kidney International or the Journal of the American Society of
Nephrology. If it's more about cardiovascular disease, I
might try Circulation first. If it's one that bridges both but is
very diabetes based, I would go to Diabetes. I actually follow the
impact factors and I also look at where similarly directed work has been
published. If some journal has taken a particular interest in a certain
area, then I might go there. And then, of course, some are just invited by
the journal—then it's easy.
What are the most challenging aspects of doing
research on diabetic complications and nephropathy and how has it
affected your ability to make progress?
In these clinical trials, the big problem is recruitment and the
heterogeneity of the populations you're studying. You have a lot of
different ethnic, cultural, and racial groups. It's possible, for instance,
that some racial groups respond differently than others. That is a kind of
confounder that complicates these studies. The other problem is keeping
people motivated. These studies take years. The first study we talked about
was three years long. So you need a team of clinical trial nurses and
investigators who have a good relationship with their patients and subjects
and can keep them motivated.
We've learned a lot over the years about the basic science but we've been
finding it very hard to translate that to therapies. One reason for that is
this is a very chronic disorder. It takes many years to evolve. Even if you
have a major new discovery, it can take 10 to 15 years to translate it to
the clinic. It's not like cancer, where you have this malignant disease,
and your treatment either works or works a bit, or it doesn't. With these
conditions, such as diabetic complications, you can only learn whether your
treatment has an overall beneficial effect by doing these trials with
thousands of subjects, and following the disorders for years.
But this is a critically important area of research. Increasingly papers on
diabetic complications are going to the top of the list of the most-cited
papers in diabetes. This is the major burden of the
disease—particularly cardiovascular complications—and
increasingly we now know that these complications are linked together. They
tend to cluster in patients, who tend to get all the complications, not
just one or two.
What do you consider the important areas of
research in your field?
We're now looking at several different areas of study. One major one is why
glucose continues to damage organs in diabetes even after you return the
glucose back to normal levels. This is called metabolic memory, and we're
trying to figure out the mechanisms of that. We've had two papers published
in the last year suggesting that this memory may be partially related to
epigenetic mechanisms. We're
trying to work out how glucose affects the genome in this way. Why is
glucose having this sustained effect on blood vessels, the kidney, the
heart, and the eyes? We think it is through these sustained effects on
Can you give us an example of one of these
potential epigenetic phenomena?
"We've learned a lot over the years
about the basic science but we've been
finding it very hard to translate that to
If you put cells in a high-glucose condition, then return them back to
normal, they continue to generate proinflammatory molecules, particularly
in a pathway known as NF-?B. These may be related to histone methylation of
the promoter region of one of the genes that codes for a subunit of NF-?B.
And the other areas you're now working on?
We're also very interested, not just in diabetic kidney disease, but in the
relationship between diabetes and heart disease. Most diabetics die of
cardiovascular disease. Surprisingly, this has not been very well studied.
The animal models are not very good. We're trying to work out the pathways
that cause atherosclerosis in diabetes. Some of these pathways that have
been identified in diabetic kidney disease—like this
renin-angiotensin system or advanced glycation end products—appear to
participate in diabetic atherosclerosis as well. Three of my recent papers
are looking at diabetic atherosclerosis and identifying some of these
pathways that are also relevant to the kidney and participating in other
You also asked what I think are important areas. One that I think is a big
issue with diabetic kidney disease is that we have a treatment—these
ACE inhibitors—but they only delay progression of the disease. They
don't cure it. We need to find other pathways critical to the disease, and
we have to find therapies that can add on to the ACE inhibitors. Recent
studies have shown that glucose lowering is pretty good for kidney disease,
but not so effective for cardiovascular disease. So we have to identify new
add-on treatments. We have a few targets, but not that many. In the next
few years, I think we'll see a significant amount of work focusing on
finding new targets and validating the few we have.
What would you like to convey to the general public
about your work?
That the outlook for diabetic complications has improved dramatically over
the last 20 years. Some of that is due to very good basic and clinical
research which I was fortunate to be involved in. People with diabetes
should not become despondent when they receive the diagnosis, because the
outlook has improved significantly for both type 1 and type 2 diabetes,
since managing diabetic complications is much better now than it used to
be, although we still have plenty more to do.
If you had an unlimited source of research funds,
what research or clinical trial would you like to do that you can't do
That's a very hard question. I think what I would now do with this modern
technology—with the big advances in epigenomics, genomics, and
proteomics—is much more unbiased analysis of the human genome and the
epigenome in people with or at risk of diabetic complications, and I would
try to identify and accumulate a much bigger panel of potential targets to
test. Those are very expensive experiments and the technology has not been
widely available. The technology is now just on the verge of being much
more comprehensive and robust.
Dr. Mark Cooper
Baker IDI Heart & Diabetes Institute
Melbourne, Victoria, Australia
KEYWORDS: TYPE 2 DIABETES, NEPHROPATHY, LOSARTAN, DIABETIC
KIDNEY DISEASE, RENIN-ANGIOTENSIN SYSTEM, ANGIOTENSIN-II RECEPTOR
ANTAGONISTS, HEART FAILURE, CLINICAL TRIALS, CARDIOVASCULAR
COMPLICATIONS, GLUCOSE, METABOLIC MEMORY, EPIGENETIC PATHWAYS,