hearts entwined

Clinical and basic scientists in cardiovascular harmony

The Wellcome Trust's Cardiovascular Research Initiative encouraged the take-up of new approaches in cardiovascular medicine.

It is easy to dismiss the circulatory system as plumbing and a powerful pump. This mechanical view extends to treatments for heart disease – rerouting pipes in bypass surgery, clearing out blocked vessels, or giving the pump a pacemaker booster.

While undoubtedly effective, traditional approaches take little account of the underlying biology. Great progress was being made in, for example, understanding the molecular control of blood pressure, yet this new knowledge did not appear to be filtering through into new treatments.

To tackle this problem, in 1997 the Wellcome Trust launched a Cardiovascular Research Initiative (CVRI). The venture funded two new cardiovascular research centres – one in Oxford and one in Edinbur gh.

"It was seen at the time that cardiology in the UK had been rather slow to take advantage of some of the most exciting scientific approaches of the last decade," says Professor Hugh Watkins, who has headed the Oxford initiative since its inception. The Wellcome Trust allocated £14 million to be spent over seven years, mainly on training. The emphasis would be on strengthening molecular and cellular expertise to tackle clinical questions at the basic level. It would also provide a foothold for clinicians and basic scientists wanting to develop a career in cardiovascular research.

"This was a critical opportunity for us," says Professor John Mullins, who heads the Edinburgh group. "This initiative allowed us to catalyse interactions between cardiovascular research groups in Edinburgh."

Tackling training

From the outset, the initiative's major focus has been on research training. "The aim was to extend the opportunities for cardiologists to gain expertise in basic science training and give them opportunities to develop academic cardiology careers," explains Professor Mullins. In practice, it allowed both clinicians and basic scientists to apply for fellowship support at various levels of seniority – studentships and training for young scientists, Research Career Development Fellowships or Clinician Scientist Fellowships for middle-grade researchers, and Senior Fellowships and Research Leave Fellowships for senior investigators. And the appointment of Professor Mullins as a Principal Research Fellow was crucial to the building of the infrastructure in Edinburgh.

"The research training fellowships for clinicians were a very important part of this programme, and they have been very successful," Professor Mullins reflects. In Edinburgh, four cardiologists, an endocrinologist with an interest in cardiovascular disease, and a nephrologist with a focus on hypertensive disorders were funded by these junior fellowships.

The Edinburgh group devised a US-style rotational programme for their students, which allows them to visit three different labs during the first year. According to Professor Mullins, it has proved very popular. "Students are very proactive and are encouraged to contribute to the design of their research programmes."

But training is not just for those at the start of their careers. Both programme leaders stress how crucial intermediate fellowships are in helping successful young clinical researchers to bridge the transition to independent investigator. "This is where we lose a lot of our clinical science trainees," says Professor Watkins. "They have an alternative – a very comfortable and secure path as a consultant physician in cardiology. You've got to be pretty focused and pretty determined [to stay in research]."

At the more senior levels, the initiative has allowed both the Oxford and Edinburgh groups to recruit world-renowned leaders in the field. "We were fortunate that we gained a lot of visibility from the CVRI," says Professor Watkins. "It became known that the Oxford programme had this endorsement and many of the good candidates chose to come here. That’s been a big plus for us."

The exciting scientific opportunities and the innovative approach to answering clinical problems have, both professors agree, attracted a remarkable pool of new talent."One of the things I really wanted to do at the outset, and I’m pretty excited that we've been able to do it, is to bring in scientists from other disciplines, people with a mathematical or physics background, or from other biological fields, to join the programme. We've had a few students over the years whom I don’t think we would have attracted without that extra edge."

The change towards multidisciplinarity is in keeping with the changing nature of biology itself. It is becoming harder for small groups to be on top of all the developments and employ all the techniques successfully. "If you want to make headway more rapidly, you have to borrow from other disciplines and move people sideways," says Professor Watkins. "If we grow everything up from the bottom, it'll take a long time."

From the outset, the Edinburgh programme embraced a broad range of areas that impact on cardiovascular disease, including endocrinology and inflammation, and identified three priority areas: cardiovascular growth and development, endothelial function, and vascular injury and repair.

In Edinburgh, cardiovascular research has achieved a dramatically higher profile. In 1990 there was no active cardiovascular research going on in the city. Now, the group is gearing up to move to the newly built Research Institute for Medical Cell Biology, located at the New Royal Infirmary on the outskirts of the city. The Centre for Cardiovascular Science, which grew out of the CVRI, will comprise a third of the new institute.

"We've established a centre that didn't previously exist," enthuses Professor Mullins. "Up until very recently we were a centre without any walls: people located in different places but with a common aim.We now have a physical embodiment of that centre which is almost complete. It is a major benefit in terms of what the CVRI has done for Edinburgh."

Fast-track to clinic

But are any of these advances changing the way clinicians see patients? Genetics plays a key role in cardiovascular disease and the Oxford programme is intent on understanding genetic susceptibility, why people have heart attacks, or high cholesterol levels, or stroke.

It is also trying to develop more sophisticated views of disease states. "The heart has always been poorly defined by clinical tools. The same for blood vessels, there’s been a tendency to look at the width of the lumen and not really know what is going on underneath."

Advances in imaging are destined to have a huge impact in cardiovascular medicine and Oxford has invested heavily in this area. Their imaging programmes include those based on magnetic resonance and ultrasound and soon molecular targeted imaging. "These are really changing the way we see patients. They are very near to clinical translation. When we make advances in these fields, it is quick and easy to roll it out into practice."

Two other areas that are hotly pursued by scientists at Edinburgh and Oxford are gene transfer and stem cell research. Gene transfer is particularly suited to cardiovascular repair, as blood vessel walls are easy to access. And both groups are carrying out research to support the clinical use of stem cells or progenitor cells, an area of huge medical promise.

"Cardiology is changing but we need to walk before we run," cautions Professor Mullins. "We need to go back one step to have the basic research knowledge before we start to move forward." Already, his group has three key scientists funded by the initiative working at the Institute for Stem Cell Research in Edinburgh. In due course, he hopes to expand these applied programmes within the newly inaugurated institute.

With the initiative soon to end, Professor Watkins reflects: "The backing has given us visibility, and that's given cardiovascular research a leg up. Even when the programme ends, we will be stronger for it because of the momentum that we have achieved with it."

Professor Mullins is equally sanguine. "For the last six years, on the back of the CVRI, we've had a major success in terms of strengthening the cross-fertilisation between clinical research and basic research. This will undoubtedly have a major impact over the next few years."

hearts entwined

Tackling training

Fast-track to clinic

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