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Dublin s Michael Dunn on Cardiovascular and Psychiatric Proteomics, and on EuPA

Michael Dunn
Professor of biomedical proteomics
Proteome Research Center, Institute of Biomolecular and Biomedical Research, University of College Dublin

At A Glance

Name: Michael Dunn

Position: Professor of biomedical proteomics, Proteome Research Center, Institute of Biomolecular and Biomedical Research, University of College Dublin

Background: Professor of proteomics, Department of Neuroscience, Institute of Psychiatry, Kings College London, 2001-2004.

Reader in biochemistry, Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, 1995-2001.

Lecturer, Department of Pediatrics and Neonatal Medicine,

Royal Postgraduate Medical School, London, 1983-1988.

PhD, University College of Wales, 1970.

Michael Dunn has been elected to be the coordinator between the European Proteomics Association and the Human Proteome Organization (see ProteoMonitor 11/25/2005). ProteoMonitor spoke to Dunn last week to find out about his research and more about his involvement with EuPA and HUPO.

What is your background in proteomics?

I've been involved with what's now called proteomics since 1978. But that was really through two-dimensional electrophoresis. So really, I come from an electrophoresis background. But all of my research career has really been looking at proteins using various analytical techniques and a lot of electrophoresis. Since 1978, I've been interested in applying these techniques to look at human disease.

We ran our first 2D gel in 1978 or 1979. At that time I was working on skeletal muscle disease. I was particularly interested in muscular dystrophy.

The big problem in those days was that one actually couldn't identify the proteins. So originally we were just looking at the patterns. And then software started to come out in the late '70s, and we got involved in software for analyzing the patterns. In those days, it wasn't really possible to identify the proteins, so we used Western blotting and antibodies. You couldn't do protein sequencing from that amount of protein in those days, so that was the big problem with 2D electrophoresis in those days.

Then, of course, molecular biology took over, and everybody thought you could do everything at the level of DNA, and in muscular dystrophy that proved to be the case. They found the gene for Duchenne dystrophy by genetic techniques, and there was no need to look at the proteins.

So around 1988, I moved out of the skeletal muscle field into the heart area, which has really been my main interest since 1988. I've been involved in using protein techniques to find out changes in proteins associated with heart disease, and also following heart transplantation.

At first that involved a lot of 2D gel work, because around that time is when Edmund sequencing became a lot more sensitive. You could take proteins out of gels and do Edmund sequencing with machines, and that's what we were doing then. Then of course mass spectrometry started, and we were involved with that. We were doing MALDI mass spectrometry for peptide mass fingerprinting.

So my background was in 2D electrophoresis, and really the first Siena meeting at which the word "proteomics" was first floated by Marc Wilkins and his colleagues — that was called a 2D electrophoresis meeting.

Where were you working when you first got into using mass spectrometry?

That was in Imperial College in London in 1988 — I was working on heart disease. Then I became interested about four or five years ago in brain disease. I started using proteomics to look at psychiatric disorders. So looking at the human brain — not neurodegeneration and things like Alzheimers, but psychiatric disorders, particularly schizophrenia and depressive disorders. We're trying to see if we can see physical changes in protein expression in the brain that are associated with different psychiatric disorders.

Are you still working on heart disease and psychiatric disorders?

Yes. So after Imperial College in London, I was at Kings College in London for three years. I was at an institute called the Institute of Psychiatry. That's really why I became interested in the brain and pshychiatric disorders.

So since I've been here at the University College Dublin, I've been carrying on research on heart disease, heart transplantation, and brain disease.

What biomarkers have you found that you're interested in following up on?

So, as I said, more recently, we've been interested in finding biomarkers that can be used as diagnostics or therapeutic targets. Really I've been in that area mainly to do with heart transplantation.

One of the main problems with patients after heart transplantation is that they suffer rejection of the organ that they received from their donor. And at the moment, the ways of diagnosing rejection are very invasive cardiological techniques.

There are two types of rejection that we deal with. One is called acute rejection, which is rejection that happens in the first few months after heart transplantation. That's diagnosed at the moment by people doing biopsies of the heart. So they pass a catheter down the jugular vein into the heart. That's obviously a very invasive and very expensive technique, and it potentially has some risk for the patient. So that limits how often that can be done.

And then there's something called chronic rejection, which is what limits the survival of heart transplantation patients in the long term. That involves a form of atherosclerosis, or coronary heart disease. That is diagnosed by angiography, where you inject a radio-opaque substance locally into the heart using a catheter. Then you use an x-ray instrument to image the vessels in the heart to see if they're constricted. So obviously, that's highly invasive again, and very expensive to do.

It would be very good if one could have blood tests for these types of rejection from patients. That's something we've been working on for some years on proteomic techniques.

We've actually found panels of markers that are potentially useful both for acute and chronic rejection using these proteomic techniques. There are several centers which now find our test a useful test to use. It's not yet a commercial test, although we do have intellectual property on it, and there are several companies that are interested.

That's probably the most successful thing that we've done in terms of biomarkers.

What kind of experiments are you doing for your psychiatric studies?

At the moment, most of those have been done on human samples. We have access to samples from tissue banks. The samples have been collected specifically from patients with schizophrenia and other depressive diseases. Then we're looking at protein expression in specific regions of the brain. That work involves laser capture microdissection. You can have a frozen section of the brain, and actually use a laser to cut out specific small regions of the brain, and you can do transcriptomics and proteomics on that.

The brains are quite rare. They come from specific centers in North America. There's one called the Stanley Foundation. That was set up specifically to do schizophrenia research. As part of that, they managed to collect quite a large number of brain samples.

We're also becoming interested in exploiting animal models. There are now some credible animal models of psychiatric disease. There are behavioral problems that these mice have that have some parallels with human disease. So we're starting to work in that area, looking at the changes in the brain in these animal models as the animal develops and matures.

There's quite a few potential markers that we've found that can be followed up. When I say markers, you wouldn't use them as diagnostic markers, but they are things that we think are associated with those disease states. Whether they would then be potential therapeutic markers is a different issue, because at the moment we don't really understand how those proteins act in pathways. That's something that we need to think about and to look at.

What are you working on in terms of heart disease?

We're working particularly on heart muscular types of diseases. We're particular interested in diseases called cardiomyopathies. They are diseases where the primary defect is in the heart muscle itself. There are two main forms: dilated cardiomyopathy and hypertrophic cardiomyopathy. In both of those, you get an enlarged heart. In one of them you get a very thickened muscle in the heart, which actually interferes with the heart pumping action. In the other one, the muscle of the heart is very weak, so you can't pump the blood around the body properly.

There are no therapeutics which cure these diseases. They can control them for a while, but eventually these patients become bed-ridden, and they die. So these are candidates for heart transplantation. That's actually why I got involved with this. Through heart transplantation you can get access to large amounts of heart tissue, when the heart for these patients is removed.

We're trying to find protein changes that have some association with the disease state, which would tell us why these hearts are dysfunctional. If we have an understanding for that then we might be able to devise therapies to address these pathways.

Can you describe your involvement with HUPO and EuPA?

I've been involved in 2D electrophoresis and proteomics since its inception, so when HUPO started, they invited me to be one of their council members. So I was one of the founding council members of HUPO. I'm not on the council anymore because I didn't have enough time to devote to it.

I've now become involved with the European Proteomics Association as the liaison between that organization and HUPO.

Really EuPA is a grouping of all the national activities in Europe in proteomics, and we will act as the main interface with Brussels, for example, in terms of the European Union, in terms of developing research strategies for Europe. And then we're coordinating with HUPO and the other large national organizations like the Chinese HUPO and the Korean HUPO.

Do you see Europe taking on any collaborative, large-scale proteomics projects in the future?

Well at the moment, we have the Brain Proteome Project, the HBPP, which is led by Europe. That started in Germany, and majority of people working on that project are from European labs.

And recently, we're starting a cardiovascular initiative. I'm the co-chair of that. The other co-chairs are Peipei Ping from UCLA and Peter Liu from Toronto. Because of my long involvement with the heart and cardiovascular proteomics, I've been invited to chair that. I'm hoping that we can involve quite a lot of European labs in that initiative.

Our first formation of that will probably be at the next HUPO meeting in Long Beach, Calif. We'll also try to have a few pre-workshops at the US-HUPO meeting in March or April of next year, and we have a meeting in Cambridge, UK, at the European Bioinformatics Institute in July.

One issue that we see as being particularly important in Europe is funding. In order to be competitive at the world level in Europe, we need to have something that's supranational, because otherwise if we just have national funding, then the pool of resources is not enough to go after major initiatives in a big way. So that was one of the ideas of EuPA — if we can lobby at the European level, that that would be much more effective.

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