One component of this pathway that you've done a lot of work on is the receptor endoglin. What did you discover when you blocked the gene for this receptor in mouse models?
This gene is incredibly important in the process of forming blood vessels and maintaining them. What we have done with the mouse models is try to mimic what happens in patients, where affected people have one good copy of the endoglin gene and one bad copy. Interestingly, mice that are heterozygous have a very mild disease phenotype. And if there is no endoglin, so when both copies are mutated, the embryos have such serious blood vessel defects that they die halfway through gestation.
Then we looked at what happened if we knocked out the second copy of endoglin in early postnatal life and in adult life. That showed very clearly that you need triggers that promote blood vessel formation in order for the defects to manifest, so angiogenesis triggers combined with loss of the second endoglin gene led to the vascular malformations associated with HHT. That told us that you need two hits to develop HHT: you need loss of endoglin and you need an angiogenic trigger.
How does this 'two hits' mechanism work in heterozygous humans to cause the diseases associated with mutations in endoglin?
We'd noticed in heterozygous mice that if there was any inflammation, that seemed to trigger problems with the blood vessels. That gave us a clue that inflammation might be involved in causing the disease phenotypes. And inflammation can trigger angiogenesis, so that's one hit.
We think that there are two ways that heterozygous patients can lose their second copy of the endoglin gene - the second hit. The first way involves inflammation. In inflammation, endoglin is cleaved off of the surface of the cell. If you're homozygous and you've got your full complement of endoglin, you’re OK. But if you're heterozygous and you’ve got only half the amount, then you become vulnerable and vascular malformations may follow. The second way is having a somatic mutation, which means that the second copy of endoglin is mutated locally in the tissue.
We're well on the way to fully dissecting the pathway that leads to vascular malformations in HHT. The goal is to use the models we've made to help develop better therapies for patients with this disease. So I'm feeling very positive about that.
You're also doing in vitro work looking at angiogenesis in cultured heart stem cells, called cardiospheres, which are known to express high levels of endoglin. How might endoglin-producing cardiac stem cells prove useful in treating heart disease?
We're investigating whether these stem cells might be useful in treating people who have had a heart attack, a myocardial infarction. Myocardial infarction causes a region of ischaemia, a region of no oxygen, in the heart muscle and the heart muscle cells start to die quite quickly. The dead tissue is then replaced by scar tissue, which can't contract, so the heart doesn't function as well and patients are at increased risk of developing heart failure.
Thus it is important to protect or rescue as much of the heart muscle as possible immediately after a heart attack. One way of doing that is by promoting angiogenesis in the affected region to improve the supply of oxygen and nutrients to that area. These cardiosphere cells, which are stem cells cultured from heart muscle, can be used to promote formation of new blood vessels in damaged heart tissue. And we found that if we knocked out endoglin in these cells, that process was much reduced. That led to a major study that we've just really begun in the last two years, which is looking at what endoglin is doing in these stem cells to promote new blood vessel formation.
Your work isn't just in the laboratory, you recently had a cameo in British Heart Foundation's TV advert 'Fight for Every Heart Beat'. Was this unusual task something you enjoyed doing?
The British Heart Foundation believe it is important to involve the scientists they fund in promoting what they do. They don't want the scientists to sit in ivory towers and not tell everyone why their research is vital for improving treatments. The actual filming for the advert was tough because it was against the clock: the whole advert had to be only 20 seconds long. It was a real challenge to say something in a convincing way and in a heartfelt way against the clock.
You started out your career working in DNA recombination and repair, then switched to genetics of cardiovascular disease when you returned to work after a break to raise your children. What prompted that change of direction?
When my youngest child went to school, I started looking for local opportunities where I could get back into science. But there just wasn't anything available at the time in the field that I had trained in. I was forced to re-think. I realised that the genetics training and experience in DNA recombination and repair had provided me with many research skills that would be useful in other areas. A lot of these skills I was able to directly translate to the genetic questions in HHT, which was an important new project at Newcastle University.
It's important to emphasise all the support that I got when I chose to return to science. My way back was through a Wellcome Trust Research Career Re-entry Fellowship. Without that fellowship award I am sure that I wouldn't have got back into a scientific research career. These days there's a lot of focus on why women are leaving academia, but grants like this give scientists an opportunity to get back into academia after some time away.
Dear Prof. Arthur, thank you very much for this interesting interview!
Interview: Helen Jaques