Professor Julie Campbell is a vascular biologist whose research has focused on the cell biology of cardiovascular disease and atherosclerosis. Her team has developed a method of growing artificial blood vessels in the peritoneal cavity of an animal into which it will be later grafted. She is Director of the Centrefor Research in Vascular Biology at the University of Queensland and Director of the Wesley Research Institute at the Wesley Hospital. In 1995 she won the Wellcome Australia Medal and Award for Medical and Scientific Research.
Interviewed by David Salt in 2003.
Contents
The foundations of a competitive scientific career
Julie, let's begin with your early life. Could you tell us a bit about your parents?
My parents were working-class people, and very hardworking. My father had to leave school when he was 12 years old to support his widowed mother and his siblings, so he didn't have a very good education. Consequently, although his shrapnel war wounds did not really affect him physically, the type of work he did was to manage a paint remover factory, Superstrip, in quite a slum suburb of Sydney – now a fashionable inner city suburb.
My mother came from a family of nine children, her father being a printer. She got a reasonable education for someone in her era, but she worked in a printery and a plant nursery. She was also a physical education teacher, a very fit woman who used to have clubs with several hundred girls, and she was quite well known in the area.
Although neither of my parents was well educated, they valued education in others. They were not exposed to science as I was, however, so they didn't understand it at all. I remember trying to explain to my mother what a cell was, but I don't think she has ever understood it.
So where did you find your passion for science?
I was a very inquisitive child, wanting to know more about everything and to know how things work. I've always been like that, just as I have always been competitive and outspoken. As a child I was a bit of a tomboy, too. Perhaps I got that from my father, who was rather a larrikin, in many ways, a streetwise type of man who could always figure out how to fix something and to find ways around things.
Are you competitive and outspoken in your scientific career?
Oh, very much so. As a child I was in a lot of trouble for being outspoken, for example at high school when the students had some beef with the headmistress. Even if I didn't share their views I acted as spokesperson because no-one else was game enough to speak out. And I don't like losing. I think the only reason I did a PhD was that a lot of my friends were doing it. I thought, 'Hang on, I'm much better than they are at science,' and I couldn't bear the thought that they would get a higher qualification than I had and then one day, when we were competing for the same job, they would get it because they had that qualification.
Your competitive nature probably helped you through primary and secondary school. In 4th grade you were selected to attend an opportunity class for high achievers. You went on to a very selective high school, surrounded again by top performers. What were those school years like?
The girls in the OC classes and at St George Girls High School, in Sydney, where I went, were brilliant. To me it seemed as though it came easy to them. I used to compete against them so furiously, trying to hide it by studying in private to try to beat them – which I never could. I think in my high school years, out of a class of 150, I would come about 15th, or sixth at best. Those girls were just superb – top of the state in many, many subjects.
To my great disappointment, not many of them have done much in their post-school life. They got fairly ordinary degrees, for jobs that really do not take intellectual capacity or provide intellectual stimulation, such as pharmacy. Probably the reason I have gone and become a scientist and a professor is not so much that I was bright but that I have a competitive nature and was always trying to be persistent and determined to achieve.
Encountering the wonder of the living organism
At the end of high school you felt quite 'wrung out', I believe, and when you went to university you chose to work for the first couple of years at the Australian Atomic Energy Commission instead of taking up a Commonwealth Scholarship.
That's correct. I got my Leaving Certificate at the age of 16, and I had a tension headache for about a month afterwards. I had been competing furiously, not so much against other girls – or boys – in the state but against my friends in my class. I wanted to beat them, and although I didn't do that I did work very, very hard. So I felt I needed a break before going to university full time, and for two years I worked on chemistry during the day at the Atomic Energy Commission and studied chemistry at night, part-time, at the University of New South Wales.
At that point you had your sights set on a career in industrial chemistry, I think.
Yes. I always intended to be a chemist. At high school I did physics, chemistry, maths I, maths II, French and English – no biological subjects at all. In fact, I did an elective in chemistry for honours, and I still love chemistry.
But when I hit university I started to do biology subjects, as you had to in first year. Probably one of the major turning points of my life was doing biology and learning about the living cell, the living organism, because it totally blew my mind. I just couldn't believe it. And I couldn't even look at a piece of wood the same again. I would see it as composed of what had been living cells, with the root system and everything. I just thought, 'My God! This is wonderful.' I became enamoured by knowledge and by science, and particularly by the living organism. And I think I still have that wonderment in relation to life and just what it really is.
Do you think such wonderment is one of the key elements of being a good scientist?
It is essential. I think you have to be almost childlike in your wonderment to be a good scientist. To be delighted in learning, in finding out things that you believe no-one else has found out before – as well as to be able to think laterally – is what makes a scientist.
A rigorous physiology honours course
The real starting point for most scientists is their Bachelor of Science. Having 'discovered' biology at university, you ended up doing honours in physiology – something quite special.
I found out years later that I was the first honours student in physiology at the University of New South Wales. I chose physiology because, even though I had majored in both chemistry and physiology, the living organism fascinated me more than the dead molecule, so to speak, in chemistry.
Professor Paul Korner was the head of department during my undergraduate years. He is the most wonderful scientist. As undergraduates we were in total awe of him. I would not say he ruled the place with an iron fist, but he was an imposing and awe-striking person, quite amazing. We used to tiptoe down the corridor, afraid to interrupt his experiments – he did his physiological studies on conscious rabbits and if we disturbed his rabbits in the middle of it, while he was recording from them, heaven help us! We would get such a verbal dressing down that we would be trembling. He was awe-inspiring because he was such a generous, wonderful man and also a fastidious and incredible scientist.
Later, you shared with him that you'd been afraid of him. What was his response?
That was much later, when I had returned to Australia and joined the Baker Medical Research Institute in Melbourne, where he was the Director. (We hadn't seen each other from the time I was an undergraduate until I had been a postdoc for several years.) I remember that we were standing at the photocopier. I had been head of the cell biology laboratory for a few years, and I was still my very outspoken and all-knowing self in many ways. When I told him how as undergraduates we had all been petrified of him, he turned to me and said, 'Well, JC, now I am afraid of you.' And then he laughed, because it was really quite funny that he had learned to respect me as a scientist as I had respected him, and also to be wary of my outbursts as I had been wary of his.
Participating in a Golden Age for smooth muscle biology
After honours at the University of New South Wales, in 1969 you went to Melbourne University for your PhD, taking up studies on smooth muscle, autonomic nerves and cell biology. What was the attraction in these areas?
I went to Melbourne because my then husband wanted to do his PhD there. I looked around at various laboratories in Melbourne and found there was so much good science going on, so many different choices, and eventually I chose to go and do my PhD with Geoff Burnstock, in the Department of Zoology. I had never done zoology in my life – I knew about cells and about human physiology, but not about little animals – but that didn't matter because the Zoology Department at Melbourne University in those days was more of a physiology department.
The reason I chose to go with Geoff Burnstock as a supervisor is that he is the most dynamic man. He wasn't a good PhD supervisor per se – and I say that guardedly – in that he didn't teach you techniques, he wasn't with you the whole time. In fact, you hardly ever saw him. But Geoff did provide inspiration in his lateral thinking, his enthusiasm, his incredibly broad knowledge. Also, he attracted the most wonderful people. The group that was there made it a Golden Age, I think, for smooth muscle biology – incredible people like Max Bennett as his PhD student, John Furness, Marcello Costa and Gordon Campbell. We interacted with each other, we learnt off each other, and we learnt from the people he brought from overseas. He created an atmosphere of learning and interaction.
He was tough, in that he would tend to put two students on the same project. They might have been best friends but he would watch them virtually fight to the death – and God, he got good science out of them. Most of us were already competitive, but he made us supercompetitive. And this resulted in two things. The weaker students failed; they just dropped off. Probably a third of his students left without getting through their PhDs. But the ones that survived were (a) naturally tough, and (b) made more tough by this environment, and now you will find his students as professors all over Australia and internationally. The quality of a person is whom they leave behind, and Geoff has left behind so many wonderful scientists.
Did you choose smooth muscle biology, or did you happen to be in a place where it was taking off, and so to take off with it?
I chose the man, the supervisor. I went to see Geoff and he inspired me. He had ideas that were just mind-boggling. His strength is that he is a visionary. I had no prior interest in smooth muscle; the work just happened to be on that.
But it has turned out to be your life work.
Oh, it has. I remember reading a book when I was a child, about two animals that got marooned on a desert island where there were only two books, one on rheumatism, I think, and one on umbrellas. And the two animals became experts on those two topics, fascinated by them. I think anything can become interesting, if you look deep into it. For me it just happened to be smooth muscle. It could have easily been something else.
Major discoveries in smooth muscle proliferation
Your postdoctoral years were spent at Melbourne University, the University College of London, the University of Iowa and the University of Washington. Would you tell us about the early postdoc years, in Melbourne?
That was the time when I made the discovery which I guess has directed my research for the last 30 years. It involves the fact that smooth muscle cells are only capable of proliferation and matrix synthesis if they undergo a reversible change in their phenotypic expression. In skeletal muscle or cardiac muscle, the mature cell cannot undergo proliferation – it has to die, and an immature cell, a satellite cell, has to come up and take its place. But smooth muscle cells can undergo a reversible change in phenotype and replace themselves. That is in all the textbooks now, and people will say, 'Well, we knew that.' But they didn't. It wasn't known until I discovered it, way back in about 1973.
Was it believed that these cells were set and would not change, regardless of their environment?
People thought that mature cells underwent proliferation. I showed that a mature cell, in its current phenotypic state, cannot do so. It had to undergo this very classical change in phenotype that altered its whole structure, and then the change in biology followed. But it was reversible. I found out also which factors stimulated that change in phenotype, and which prevented it. And I recognised, at that point, how important this was for vascular disease such as atherosclerosis. In atherosclerosis, and in restenosis after angioplasty of primary lesions, we get an overproliferation of smooth muscle cells. But if we could prevent this from occurring, we could prevent disease from occurring. I think one of my major contributions to science is in this very basic cell biology area within smooth muscle.
You knew at the time that these breakthroughs you were making were important. Did you also know that the rest of your career would follow this course?
I don't suppose I really thought about it. But you do try to find more and more about the topic. In fact, my interest now is still in smooth muscle but in something slightly peripheral – not so much the phenotypic changes of smooth muscle, but how other cells can turn into smooth muscle. A second part of the dogma about the mature cell, when I was going through my PhD and postdoc years, was that cells could not transdifferentiate into another cell type. But my research now is showing that a cell of bone marrow origin – in particular, a fully differentiated macrophage – can transdifferentiate into a fully mature vascular smooth muscle cell. So my work has moved laterally, but it is still closely related to the cell biology of smooth muscle.
Postdoctoral travels and achievements
What were some of the highlights of the postdoctoral years you spent overseas?
First of all I should say that my first marriage did not last very long – I was only 22 and just far too immature – I then married Gordon Campbell, one of my fellow PhD students in Melbourne. We both undertook postdoctoral positions in the United Kingdom and then in the United States, and we got married in Iowa.
When you went on those overseas postdocs, were you choosing certain locations or people you wanted to work with, or both, or were you taking any opportunity and then making the most of it?
Both Gordon and I went to London for a year because Geoff Burnstock had recently moved to University College. The aim was to work in London with some of the collaborators that I had met through Geoff, especially Professor Ute Gröschel-Stewart. It was easiest for us to work in Geoff's facilities and for Ute to come across to there from Wurzburg, Germany. So again I was taking advantage of the opportunities that Geoff Burnstock gave to me and to Gordon, for which I am extremely grateful.
In the United States we went to the University of Iowa for about nine months, more for Gordon than for me. There I had a huge fight with the person we ended up working with. I stormed out of his laboratory and refused to work with him because he was a charlatan, an impostor. We actually disproved the hypothesis on which he had based his reputation, but he refused to even consider our crystal clear evidence.
Being still captive, so to speak, in Iowa, I had to decide what I was going to do next. I thought, 'Okay, I shall gather up all the knowledge on smooth muscle biology and phenotype and put it together.' That review on the smooth muscle cell in culture became a 61-page article, virtually a thesis, which was the summation of knowledge at that point, including all my own ideas on smooth muscle phenotypic change and its importance to atherosclerosis. It has become a Citation Classic – I believe it has had over 1080 citations. It is still referred to these days by everyone in the smooth muscle biology field.
We then went to the University of Washington in Seattle, which was where I really wanted to go when I was in the US. We worked there with some marvellous people: Russell Ross, Steve Schwartz and so many other people who are absolute masters in smooth muscle biology.
Research consolidation in a stimulating environment
On your return to Melbourne in 1978, you and Gordon both secured positions at the Baker Medical Research Institute. As head of the cell biology laboratory, what work were you carrying out?
It was a continuation of the smooth muscle biology in atherogenesis that I had started in my postdoctoral years. It was during that time that I really thoroughly categorised and characterised the change in smooth muscle phenotype and what controlled it, how the biology of the smooth muscle cell changed with that change in phenotype, and how that was a crucial event in the development of the atherosclerotic lesion.
So it was a time of consolidation, in a sense, in that you had made the breakthrough and now you were following up and colouring in the picture?
That's right. I was also exposed to some wonderful people. Paul Korner had taken over as Director of the Baker Medical Research Institute in 1975, while I was still at the University of Melbourne and before I had gone on my postdoctorals. And in the next few years he virtually took a broom and swept out the old guard at the institute, bringing in a new guard which included Gordon and me. We were all in our early to mid-30s, people like Warwick Anderson, Elspeth McLachlan, Jim Angus, Tom Cocks, Garry Jennings, Murray Esler. Many of these are Fellows of the Academy. Paul Nestel was there, Noel Fidge, Alex Bobik. We were all working on different aspects of the cardiovasculature but Paul Korner provided the most stimulating environment, where all of us, of approximately the same age although some were 10 or more years older, flourished – wonderful groups. Paul provided that fertile ground for us to have our own head and to follow our dreams and where we were going in science.
Synergies between science and personal life
You were at the Baker Institute throughout the 1980s. What were some of the personal life landmarks for you during that time in Melbourne?
I had three children, one in 1978, one in '80 and one in '81. My first child was 3½ months premature and was a very sick baby. (He is now 24, a big strong lad just finishing his nursing degree. And he is fantastic.) At one stage I had three children aged under 2½. Being the type of person I am, and even though my eldest child was premature and spent his first five months in hospital – I also got a pulmonary embolus as a result of this pregnancy – I took no more than three weeks off for the birth of each of my children. I was so passionate about my science and I was still so competitive that I felt that, despite being a woman with children, one of them very sick, I could not expect any special consideration. I did not think people could say, 'Ah well, it's okay. She's got all these problems. We'll just let her off and we'll give her the grant' – you are still competing against men who aren't mothers. They might be fathers but they don't have the nurturing issues that women do, or the physical problems of carrying and bearing the child, and getting a pulmonary embolus afterwards. But I felt that my competitive nature caused me to be even stronger during that time.
I don't think I was a bad mother. I think I have been a very good mother. My children are all healthy, happy and non-drug-taking, all university students and very strong individuals. I think that in a way I am a role model for them in that regard.
I was fortunate that my mother, who was widowed, came to live with us. She was an incredibly wonderful support for my children in their early years. My oldest boy is now repaying the care that his grandmother (now 82 years old) showed him as a child, by looking after her marvellously, like nothing on earth.
Just on another aspect of your personal life: your husband Gordon is working in a related field but not exactly the same field as you, I think.
Actually, we work together – as we have virtually ever since our early postdoctoral years. He is a Professor of Anatomy; he is structure. And I am a physiologist; I am function. I guess we bring different disciplines and different ways of thinking to the same problem. We work hand in hand.
When you are both choosing your next step, the next location, next lab, you presumably have to compromise at times and maybe not go to your own first choice. By the sound of things, that has worked well for you – you have taken on every opportunity and made the most of it. Has this been a good partnership with Gordon, professionally speaking?
Yes, it has. The decision whether or not to go to Iowa was probably the major one. When we returned to Melbourne we were now married and we both joined the Baker Medical Research Institute. I stayed there for 13 years; he stayed for about two years, because he got a senior position in the Anatomy Department at the University of Melbourne. Anatomy was only 20 minutes away, anyway, so we still collaborated.
In 1991, however, he was offered the Chair of Anatomy at the University of Queensland. I was very well known in Melbourne in my field and I had set up a great lab and had lots of grant money and was really humming away, and our three children were still young. But because he desperately wanted this position I said to him, 'I will move for you once – once only. This is it. Do not ask me to do it ever again.' And we managed to get the children into the Brisbane Boys and Girls Grammar schools, so their schooling was not interrupted. If we were going to move, that turned out to be a good time to do so.
From established success to determined pioneer
How would you summarise the professional highlights of your Baker Institute years?
In relation to my work I think they were the consolidation and proof of my hypothesis, and the fact that I started to get invited to speak at international symposia and to become very well known internationally.
I think the highlight in my professional development was becoming part of the system of the National Health and Medical Research Council. I became a Senior Research Officer, getting my first grant with NHMRC, and then a Research Fellow, a Senior Research Fellow and finally a Principal Research Fellow. I am still a Senior Principal Research Fellow of NHMRC. I have been continuously employed by them ever since 1979. It is fantastic for me personally, to have that employment.
When Gordon took up his position in the University of Queensland, however, you found yourself in an institution where you were not as well known and your international reputation in Melbourne did not give you the prestige that you probably deserved. In Queensland you set up your own lab, the Centre for Research in Vascular Biology, but you have described its establishment as a year of frustration.
It was quite a shock to me that in the first few years in Queensland I was treated like my husband's handbag. He was the big professor and although I was probably better known than he was in Melbourne, suddenly I was just an attachment. That hurt my ego something chronic! Again my competitive nature came to the fore. I set up my own Centre and got my grants, and I built that up from nothing to be a highly successful centre. But it took a few years for the powers that be at the University of Queensland to get to know me and to know what I could actually do – even though I was a Senior Principal Research Fellow of NHMRC and there are not that many of them in Australia, let alone at Queensland University.
One thing that proved my worth was winning a prestigious award, the Wellcome Australia Medal, in 1995. I was the first Queenslander ever to win that. It was a bit of an eye-opener and I think it changed my professional standing to some extent. Also, the lab itself was coming up with significant results. And I personally was bringing in more than $500,000, sometimes $700,000 a year in grants. I'd have thought that would have helped, but again you have got to get their notice.
I suppose that getting the right people, the right equipment to build a laboratory from scratch is frustrating. If things have improved now, do you feel that you have played an important role in that turnaround?
It wasn't easy. At first there wasn't a great wealth of talent for research assistants and students in Queensland. It was hard to get quality people. But that has gradually changed. Queensland is now the most fantastic place for biomedical research, whereas in the early 1990s it was only just starting to happen.
I have been one of the people bringing that change about. I think things act as a juggernaut. You get a few good people, they attract other good people, and it just goes on and on. There are wonderful people now in all aspects of science in Queensland.
I imagine that to set up, from scratch, something that became important and part of the momentum of the place would be enormously satisfying and fulfilling.
That has always been an attraction to me. I have always preferred not to go into an area that was mature and running smoothly. I have always liked to begin, to be the pioneer, and to develop the field, to develop the laboratory, to develop whatever it is going to be. That gives me a buzz.
In 1996 you took on, in addition to all these other things we are speaking about, the role of inaugural Director of the Wesley Research Institute, at the Wesley Hospital. What was the aim of this institute, and your role in it?
The Wesley Research Institute was begun in 1994, just by a group of people at the Wesley Hospital who felt that the hospital required a research culture. For the first two years it functioned on a fairly ad hoc basis, with a caretaker person as the Director but not with any real authority. They then advertised for a part-time Director, which was all they could afford. My husband saw the advertisement and said I should apply. When I asked, 'Why? Do I really need another job, an additional job in what I'm doing?' he said, 'Oh, you might find it interesting to have a clinical perspective.' So I did apply, in fact the only non-clinician, the only true scientist to do so. And I think they saw the worth of having someone with very strong scientific training to direct a clinical research institute. I took that on, doing it 1½ days a week – officially 10½ hours, but really there's a lot of nights and weekends involved as well. It's an enormous job and should be full-time.
We encourage, support, direct and administer about 25 investigator-driven projects and eight clinical trials, and only last year we became the institute of all five Uniting Health Care hospitals in Queensland – potentially, of many thousands of visiting medical officers.
You brought a suite of skills to this position. Did the position impact upon the way you did the rest of your research?
I think it educated me. It made me a broader scientist. I knew a lot about the cell biology of the cardiovascular system but I didn't know very much about neurology or breast cancer or prostate cancer, or wound healing in bones, or, in particular, quality of life issues. In fact, I used to think the social sciences were pretty soft. But I came to appreciate that social science can be very exacting, and I strongly encourage the nursing staff to do research into quality of life issues. I think it has broadened me and made me more appreciative of different disciplines.
The development of artificial arteries
Your current set of investigations, in a way, brings together many of the threads we have been discussing. This is centred on the development of artificial arteries. Could you describe what these are?
The seed of this work developed in the early '80s, when Gordon and I were putting pieces of foreign bodies – for example, boiled blood clots or boiled egg whites, or gelatin, or even bits of glass or wood – into the peritoneal cavity to initiate an inflammatory response, to form a myofibroblast capsule around the outside. A myofibroblast, which causes wound contracture in the skin, was always thought to be halfway between a fibroblast and a smooth muscle cell. If you cut yourself, cells in the periphery, on the edges of the wound, become myofibroblasts which become contractile, and when they contract they bring the edges of the wound together. But there was some controversy on their cellular origin. So we were putting this foreign body in the peritoneal cavity – as other people were – to develop myofibroblasts and study their biology.
We noticed not only that the capsule that developed consisted of myofibroblasts but that on the outside there was a layer of mesothelium, the cells that line the peritoneal cavity and have properties very similar to endothelial cells that line blood vessels. They secrete prostacyclin and nitric oxide, supposedly so that they can cause a vasodilatation. They also form a frictionless surface in the peritoneal cavity so the guts can slide around and not stick, just as the endothelium provides a frictionless surface so the blood cells can slide down the lumen. So we had the foreign body, then a layer of these myofibroblasts, and the mesothelium on the outside.
When we did these studies we said, 'Gee, that looks like an artery, but with the cells that normally line the lumen on the outside. It's also a sphere, a solid body. Perhaps we could grow that in a tube structure and make an artery out of it.' Because we were doing so many other things, though, we just put it on the backburner. It wasn't till 10 years later, when yet another PhD student came to us and we were running out of PhD projects, that we thought, 'Hmm, why don't you put some tubes into the peritoneal cavity and see whether you can grow this myofibroblast capsule and mesothelium in the form of a tube?' And the student, Johnny Efendy, did so and found that was what happened.
We then harvested it from the peritoneal cavity and turned it inside out, removing the inner piece of tubing. What we got was a structure that had now the mesothelium, or pseudo-endothelium, lining the lumen of this tube of living tissue. Nothing else. And when we transplanted it into high-pressure arterial sites, we found that it differentiated further into an arterial structure.
We are now doing this in dogs. A piece of tubing 4.5 mm in diameter, which has been in a dog peritoneal cavity for three weeks, can have a capsule formed on the outside which is about 1½ mm to 2 mm thick. That's a pretty strong piece of tissue.
This is now big news, I gather, and it has led to your revolutionary lateral step.
Yes. Recently we have also proven that the myofibroblasts that we were studying years ago, wondering about their origin, are in fact derived from peritoneal macrophages. By using transgenic mice that you can get these days with specific labels for macrophages, we can trace their lineage. So, using new technologies, we have now come to solve a question that we were looking at in the '80s, and have been able to develop these artificial blood vessels.
Grow-your-own designer blood vessels
All this amazing stuff began with the observation that what was happening around those foreign objects looked a bit like a blood vessel. Are you the first people to have made this observation?
Yes, that we know of. People might have said it but not published it. We saw it, we published it, and we did something about it. That's what makes the difference.
Are there other ways of making artificial blood vessels?
A number of laboratories overseas have been trying to grow them in culture, but you have to sacrifice a healthy blood vessel to grow those smooth muscle cells and endothelial cells and then re-seed them into various biodegradable structures. We can grow ours in the peritoneal cavity or the pleural cavity of the person or animal that is going to get that transplant. So it is an autologous artificial blood vessel and there is no rejection.
When you take some healthy blood vessel out of the body and grow the cells in culture, the cells lose a lot of their antigenic properties. Then, if you put the artificial vessel into a bioscaffold and back into the animal or person, the host recognises that as a foreign body and can reject it. The fact that we are growing and transplanting it in the body means there is no rejection. Also, our tube of tissue grows from almost nothing, just cells floating in the peritoneal cavity, to this required structure within two to three weeks. Growing tissue-engineered blood vessels in vitro takes months. So we think we have done something a lot better.
We call these structures grow-your-own blood vessels, or grow-your-own designer arteries, and we can grow them very long. In fact, we have now developed a device whereby we grow the myofibroblast capsule inside an outer sheath that is adhesion resistant, so we don't get any problems, and has holes in it. The cells are attracted through holes into a biodegradable matrix around an inner polyethylene tube. We grow these in dogs to about 25 cm long.
The procedure is really quite non-invasive. We do a small incision, under general anaesthetic, in the linea alba and then a small incision in the peritoneal wall. We put the device in the peritoneal cavity, with a flange which sits flat against the peritoneal wall. We put purse-string sutures around the outside of that little incision, pull it tight so there is no leakage, and then just sew up the skin. The device, which has to be free-floating, just dangles free in the peritoneal cavity. Two to three weeks later, we come back and, under local anaesthetic, just do a very small incision, cut where we have sutured the flange down to hold it flat, pull it out, put a couple of sutures in to sew up the hole and then sew up the skin.
We can then transplant the new vessel as a vascular graft. In the dogs we have been transplanting it into the femoral artery as an interposition graft, and we have kept it there for many, many months. When it is transplanted into that high-pressure arterial site, it undergoes further development, further differentiation, such that it becomes identical to an adult vessel. If a sample of the blood vessel is stained with antibodies to smooth muscle myosin, you can see a media, an adventitia, even vasa vasorum, the small blood vessels in the adventitia. So it becomes almost exactly like a native blood vessel.
New prospects in renal failure treatment
This is not some pure science breakthrough that might have an application in 10 years' time, but something that you have already occurring on test animals. When might it be applied in human cases?
Well, we are currently testing this prototype device in dogs, and we have got to get our numbers up such that we have zero per cent adhesions and 100 per cent myofibroblast capsule formation that is strong enough and will not undergo aneurysms or burst. I think we will have done that by September this year, and at that point we will go into humans. Through my contacts at the Wesley Research Institute and through the Wesley Hospital I have already teed up clinicians – a urologist and a nephrologist – and vascular surgeons who are happy to collaborate. I have also spoken to the ethics committees about what they require before we are allowed to go into humans. As long as we have got the dogs 100 per cent, we may put these devices, or slightly modified devices, into human renal failure patients before the end of the year.
And why renal failure patients?
Those patients often have peritoneal dialysis catheters placed in their peritoneum, so this could be put in at the same time. It is an extra tube being put in, but in circumstances where they are having something done anyway. And this type of patient, I think, has the potential of benefiting most from our discovery of an artificial artery, because they would eventually go on from peritoneal dialysis to haemodialysis. For that, currently, some saphenous vein is taken from the patient's leg and placed in their forearm as an arterovenous access fistula. This is a loop of about 15 cm of blood vessel that has to have an 'in' and an 'out' catheter inserted for their blood to be taken out three times a week and put back in when the toxins have been taken from it. Imagine having a blood vessel – a vein, indeed – punctured by quite a large catheter three times a week for the rest of your life. The vessel becomes fibrosed and blood clots form, and it does not last very long. Then the patients have to have an operation in which their other saphenous vein is taken out, as a replacement. And when that dies, they have to have prosthetic grafts put in, made out of PTFE or dacron, but those tend to kink and thrombose badly.
We believe an end-stage renal failure patient can grow their own haemodialysis access fistula to be put in their arm. We don't know how it will respond to many punctures, but when it does eventually wear out, they can grow a new one. We know from our animal studies that we can grow a new capsule every two to three weeks, so fistulas can keep being grown as they are needed.
We call these 'designer' arteries because we can grow them to whatever length or diameter you want. We have grown them as narrow as 1.5 mm, in lumen dimensions, and as big as 7 mm in diameter. We have grown them 30 cm long; we have grown them 10 mm long. We have not grown branched ones yet, but I see no reason why we can't. It just depends on the mould that we put in.
Potentials and patents: aspects of a new age of bioengineering
There would be a thousand other applications, as well as to renal patients, once you had proof of concept that you could do it in humans.
If we can grow this as long as we believe we can in humans – maybe even 45 cm, given the size of the human peritoneal cavity and the fact that being very flexible this can go between the bowels, perhaps even in the form of a coil – we could use it for below-the-knee arterial replacements, for accident victims, for smokers or diabetics who have peripheral vascular disease. A potential use may be as coronary artery bypass. In fact, we have grown these not just in the peritoneal cavity but in the pleural cavity, where the heart and lungs are – the same body cavity where they are actually going to be a bypass graft for the arteries of the heart.
This research suggests the dawn of a whole new age of bioengineering. I believe you have taken out two patents connected to it.
Yes. My husband and I – he is the co-inventor – first of all formed a company, VasCam Pty Ltd. The University of Queensland is the entity that set that up because all the intellectual property is owned by the university. We have two patents, one for the concept of growing the artificial blood vessel and using this type of device to grow it in, and another one for using body cavities as an incubator to grow artificial organs. Indeed, recently we have been growing not just artificial arteries but also artificial hollow smooth muscle organs that are visceral in nature, such as bladders and vas deferens. We are also going to do ureters.
Starting a new vascular biology society
Of all your many achievements, you cite your role in founding the Australian Vascular Biology Society in 1992 as being one of which you are most proud. Would you tell us a little about the society?
I had been invited to conferences internationally in relation to atherosclerosis, and also a burgeoning international group had conferences on vascular biology as a bit of an offshoot. But there was no actual international society of vascular biology. There was a group in Europe and a loose group, not a proper society, in the United States. In Australia, the only national meetings at which vascular biology was spoken about were the Australian Atherosclerosis Society meetings. I had been a President of that society, but it used to frustrate me no end that most of the discussion was on lipid biochemistry, with very little vascular biology. To me, atherosclerosis was mainly vascular biology, yet I had no-one to talk to at these meetings. The work on it that was presented was basically the work from my laboratory and Gordon's.
So I decided to start my own society. Rather cheekily at an Atherosclerosis Society meeting I got up and said, 'I want to form a vascular biology society. Who's interested? Meet with me at lunchtime and we'll talk about it.' And to my amazement a number of people came. We began the society and I became its inaugural President. I raised money, and together with some crucial people – mainly Peter Little, from the Baker Medical Research Institute, who became the treasurer, and also Gordon – we really got that society going. I was the organiser and chairman of our first meeting, which we held the following year in Caloundra. It made a great profit and kick-started the society. We are now in our 11th year. The society has had 90 members for quite a long time, and is extremely active.
In 1998 I managed to bring the international vascular biology meeting to Australia, mostly through pressuring my overseas colleagues. It had been held every three years in either Europe or the United States, but I said, 'Hey, how about Asia? How about the Pacific Rim?' I formed an alliance with the Japanese and we held the first one in Cairns, with myself as chairman. That brought the best people in vascular biology to Australia and exposed our young scientists to them. Many now have gone overseas and done postdocs in a lot of those people's laboratories.
Scientific obligations and rewards
I am surprised that you have any spare time, yet you give your time also to a large number of boards, panels and committees. These include the Academic Board of the University of Queensland, the NHMRC Grant Review Panels, the NHMRC Training Awards Committee, the Cardiovascular Health Advisory Committee of the National Heart Foundation, the Council of the Queensland Institute of Medical Research and the National Association of Research Fellows of the NHMRC. And you are the founder and inaugural President of the Australian Vascular Biology Society. You were President of the Australian Atherosclerosis Society, and you are currently Chair of the Queensland Fellows of the Australian Academy of Science and a Council member of the Academy. Being so involved comes at a cost. What is the motivation?
Yes, there is a cost. But remember I am not doing all of them now – although sometimes I have done several of them at once. I have done several other things as well, I might add. For instance, I am on the recently formed Queensland Council for Medical Research.
I am not unusual in this regard. I think most scientists freely give of their time to their fellow scientists, for no pay, to forward the cause of science. It is just part of our ethos that this is what you do. If you are asked to review grants or to review papers, you spend your weekends doing it. It's just what we do. I guess we do it because we love it, it's of interest, we learn things. If we review someone else's grant or paper, we learn something from it. But it is also a service. We expect other scientists to do this for us, therefore we have to do it for them.
You have mentioned being awarded the Wellcome Australia Medal, which was for your many contributions to cell biology of the artery wall in health and disease. Do awards like this have significance for science in general?
Oh yes. Scientists don't get terribly much public recognition, although perhaps they are starting to now – the Queenslander of the Year and Australian of the Year were both scientists. I guess the general public doesn't think of scientists as real people but as nerds. Even my children think of scientists as being slightly nerdish, in spite of getting a bit more that way themselves as they become more mature and interested in science. I think these public awards are very important to showcase what Australian scientists can and do contribute to knowledge.
Besides having a jam-packed professional life, you are also a mother of three university students, you care for seven dogs and, with your husband, you run two cattle properties. On top of that you are a passionate rugby fan.
I am. Up the Wallabies!
I agree with you that a busy scientist often has a busy extracurricular life as well, but what is your modus operandi that allows you to fit all this in?
I'm organised – and I guess that's it. When I get up each morning I know what I have to do, and just do it. You just fit it in.
Maybe it is more than that. I have read that you have said an important ingredient of making it in life is 'fire in the belly'. Where do you get your fire in the belly?
I think I was just born with it. I have always had it. I have always been a bit of a rager and I just put enthusiasm into everything I do. Either I do something properly or I don't do it at all. That's what I try to infuse in my students and my children: 'If you can't do it properly, just get out of the way and put someone there that can.'
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