Regenerating science the ARMI way

The Australian Regenerative Medicine Institute is a $153 million investment in science that, when up and running and at full capacity, will become one of the largest regenerative medicine and stem cell research centres in the world.

Established through a joint venture between Monash University, which has committed over $100 million to the project, and the Victorian Government, which has thrown in another $35 million, with a further $15 million from the Federal treasury, the centre is an associate member of the European Molecular Biology Laboratory (EMBL), established 30-odd years ago to harness the scientific talent of the disparate continent.

The ARMI’s new deputy director, developmental biologist Professor Peter Currie, is understandably excited about his new challenge, which will see him (and his zebra fish) back in his home state after many years at the Victor Chang Cardiac Research Institute in Sydney. “These sorts of opportunities, to build an institute like this, of the scope and size that we are envisaging, do not happen every day,” Currie says.

The idea of ARMI started over a decade ago when internationally renowned muscle and stem cell biologist, Professor Nadia Rosenthal, first visited Australia from the US. “I was immediately struck by the place – I just loved it,” she says.

Rosenthal went on to establish several close ties here, with collaborations in Melbourne, Perth and Sydney. The longest standing of these is with muscle biologist Professor Miranda Grounds at the University of Western Australia, where Rosenthal has spent significant periods of time since as a visiting professor.

What also became established over her first few trips to Australia was an idea for what would turn out to be one of Australia’s most ambitious and potentially prestigious new research ventures.

“During my early time in Australia and through talking with many different people, I was struck by the issues that Australia faced in terms of the brain drain and insufficient scientific opportunities here compared to other places such as the US and Europe,” she says.

These issues reminded Rosenthal of those faced by Europe in the 1970s, with our federation of states somewhat equivalent to the fiercely independent member countries of the EU. That continent addressed the problem at the time by setting up the now highly prestigious European Molecular Biology Laboratory (EMBL) in Germany, and history shows that the EMBL model has worked well for the re-invigoration of European science.

One element of the EMBL model in particular has attracted both Rosenthal and Currie: the well-developed system of encouraging and retaining young scientists.

---PB--- I had a dream …

Rosenthal was aware that the EMBL had an associate membership scheme, established many years before by former director-general and close colleague of Rosenthal’s, Fotis Kafatos.

“Fotis wanted to broadcast the model that EMBL has successfully employed for 30 or so years, whereby fixed-term contracts are partnered with a generous package so that young scientists have a good decade of solid support to really get their careers established, and initially take the risks that they would otherwise be hard pressed to take if they had to support themselves just on soft (peer-reviewed grant funding) money,” she says.

So, Rosenthal decided that what Australia needed was to become the first associate member of EMBL, and, ideally, establish an institute centred around this membership. “The EMBL model inherently creates a very dynamic scientific environment that often becomes a springboard for further success,” she says.

“A similar set-up in Australia would mean a small, but reliable source of well trained scientists in various disciplines that would be ready to take on leadership roles here and not need to go overseas.

“Australian science has in the past tried to build critical mass over and over again in different places rather than trying to find a way to do it together, which of course is somewhat because of the tyranny of distance … and somewhat because of the decentralised funding systems.”

Rosenthal also feels strongly about better emphasising and supporting young scientists at a time in their career when they are likely to be most productive. “Once overseas, they often stay there because trying to get back into the Australian system is nigh on impossible – again a lot like Europe all those years ago.

“Australia is growing scientifically, and more than ever it needs its own ready source of accomplished scientists. If you build something and bring enough good people together in an institute you can change that culture of automatically leaving. It is changing, but concentration of research into dedicated and excellent institutes is absolutely critical.”

Currie also strongly believes that the system that is most broken in this country is this transitional period from a successful postdoc to group leader. “It just seems to take forever to get enough runs on the board to be a continuing self-sustaining entity, and there seems to be no reason for it,” he says. “If someone has done very well in their postdoctoral years, they should be able to get grants and go on to do independent research.”

Currie feels that ARMI will help in this regard by showing a new way. “What the EMBL model does is say, ‘OK, you have done well enough for us to take a punt – here is all the infrastructure, facilities and expertise available to progress your career plus five years’ money. And if you do really well with that here is another four’.”

---PB--- Words into actions

When Rosenthal put her idea to Kafatos, he was immediately supportive, particularly after visiting Australia himself and seeing the unique opportunity to recapitulate the EMBL model in a way that took all the best bits and modified them to suit.

She initially spoke to a lot of people in a lot of places to identify a scientific niche in Australia for her planned venture. “I wanted to know the strengths and the holes in the fabric, and how EMBL could contribute. I was also very interested in finding the unique opportunities in Australia that EMBL does not have much experience with, and there are plenty of them.”

Rosenthal found three examples of areas where EMBL could benefit enormously from a close association with Australian science. “Firstly, the environment here for doing stem cell research - it puts Australia in a very powerful position right now that will not last for ever.”

The second thing is the strong and well-established history of medical database building in Australia, such as the Busselton study in WA, which involves well-defined communities with enough founder genes.

“Thirdly, biodiversity is a big thing just sitting there. With the genomic sequencing revolution going on, it is only a matter of time before you can basically do a really interesting study on any number of very closely related and ancient organisms that do not exist anywhere else.”

Then Monash University came into the picture, and stayed there. This was for a few reasons, according to Rosenthal, some of which were almost due to chance. Scientifically, Rosenthal’s focus in regenerative biology matched that of several ventures and groups at Monash, particularly in the area of stem cells.

Then, coincidentally, Rosenthal had come to know Monash’s deputy vice chancellor Edwina Cornish and vice chancellor Richard Larkins quite well. “When I talked to them both about it, they were both extremely supportive and loved the idea from the get-go. They were also very instrumental in pushing it and at the last minute were really the ones that made it get over the line.”

According to Currie, Monash was also very keen to maintain its cutting-edge position in the regenerative medicine and stem cell fields, and realised that ARMI could extend and raise their credentials in that regard. Finally, and probably most significantly, Monash University and the Victorian Government came up with some cold hard cash to make the idea a reality.

Rosenthal wanted to particularly acknowledge the Group of Eight universities in Australia, saying they were “extraordinarily helpful and supportive in this whole process, from the very initial stages of us approaching the government, to getting consensus and statements of interest from all of the states and universities in Australia.

They really were a tour de force, and they deserve an enormous amount of credit for making this happen.” She also acknowledged “some very enlightened local political figures who really pushed hard.”

---PB--- Oz-EMBL is born

From then, it only remained to work out the details…this of course proved to be the hardest part, involving government, university and EMBL bureaucrats working out a deal that was financially and logistically satisfactory for all.

Rosenthal admits that at times it looked like the whole thing would fall over, but finally a deal was signed and the Aussie EMBL was born. Rosenthal was officially announced as director in May 2007 and the associate EMBL membership activated in March 2008.

The institute will sit within Monash University’s umbrella as the first node of the EMBL-Australia initiative. According to Currie, ARMI will house the first EMBL partner laboratories and form a shell within which the EMBL model will take shape.

The three other nodes are at the University of Queensland, the University of WA and the University of Sydney. Although the final details of these other nodes are still being finalised, they have all paid their membership fee and have a seat at the table for discussing how EMBL Australia will move forward.

“A lot of what we are doing at the moment is building core resources, a very important part of the EMBL model,” Currie says. “We want to make sure they are cutting edge and world’s best in the areas we are interested in.”

These include a fish facility that will be one of the largest and best in the world. Currie is understandably very excited about this particular resource and is personally overseeing the fit-out.

To satisfy another core facility, the existing microscopy unit at Monash will be upgraded and fitted out with a host of new equipment and imaging capabilities, especially in confocal and quantitative microscopy. A third major resource focus of ARMI will be in cell sorting, which is already a major strength of the Monash campus.

The institute will be fully up and running in the New Year, according to Currie, who is the man on the ground at the moment with Rosenthal still active in her roles in Italy and London. The actual building will be finished by the end of this year, and he and Rosenthal are busy recruiting at the moment to fill it.

They plan to have around 100 people joining the institute over the first two years, in addition to faculty members already involved in regenerative medicine research within the Monash biosciences precinct.

Eventually there will be six group leader positions funded by ARMI – young and talented postdoctoral fellows who will be given the full EMBL package of salary, running costs, technical help and students.

“Basically, they do not have to write grants if they don’t want to, with the expectation that they just go hell for leather for up to nine years,” Currie says. “The main selection criterion will be excellence in research. Senior faculty including Nadia and myself will be available to mentor the younger group leaders that come in, although in practice they will be totally independent.”

In terms of a ‘vision’, Currie sees ARMI as ground-breaking for Australia in terms of its product - not only excellence in regenerative medicine research, but also young inspirational scientists ready for more.

“We also see ARMI as a conduit out to Europe via EMBL’s massive network of scientists (about 1300 scientists in 60 countries),” he says. In fact, ARMI has just put its first group leader into EMBL’s main lab in Heidelberg. This is one of two planned positions permanently placed there or at any of the EMBL outstations for five years, with a further four years back in Australia.

“Of course, this is the first time this has happened so we are all sort of making it up as we go along,” Rosenthal says. “But, there is a sense that if we get it right, then the Australian model will hold for other future associate members of EMBL. Basically, we want it to serve the purpose of Australian science as best it can.”

---PB--- Mouse model

Nadia Rosenthal has an international reputation in the field of cardiovascular and muscle regeneration. Her research concentrates on embryonic heart development, ageing mechanisms and stem cell-driven regeneration of neuromuscular and cardiac tissue, using the mouse as a model.

Started her undergraduate studies in Wales, she moved to finish her degree at Harvard University in the US, attracted by its program in biology. Undergraduate research mentor and future EMBL Director-General, Fotis Kafatos convinced Rosenthal about the need for the emerging DNA techniques in developmental biology.

Rosenthal subsequently did her PhD in molecular biology at Harvard. During this time, she was involved in sequencing the first mammalian genes encoding insulin and globin.

Following her graduate studies, Rosenthal took up a postdoctoral fellowship at the National Institutes of Health in Bethesda, where she made a crucial discovery in genetics: she found the first human enhancer sequence – parts of DNA that regulate the turning on and off of actual genes.

She then returned to Harvard to focus on muscle cell development and particularly the role of IGF-1. She spent the next 16 years there wearing many different hats, before leaving the US in 2001 to head the EMBL mouse biology program in Monterotondo, Italy. She also holds a professorship in cardiovascular science at Imperial College London and a visiting professorship at the University of WA.

Over her career, Rosenthal has identified new functions for IGF1 in normal and ageing muscle and in diseases such as muscular dystrophy and cardiomyopathy. She also showed that IGF-1 is particularly important in the regenerative response, and was the first to demonstrate that stem cells within muscle fibres can be mobilised to travel large distances for regeneration of damaged tissue. These studies have suggested new avenues for therapeutic strategies in skeletal and cardiac muscle regeneration.

Fish model

Peter Currie will take up his ARMI post in December. He is currently laboratory head of the developmental biology program at the Victor Chang Cardiac Research Institute in Sydney and previously worked in the Medical Research Council's human genetics unit in the UK.

Currie has a highly successful research career, with regular publications in the leading journals of developmental biology and regenerative medicine. According to Rosenthal, he also has a strong desire to mentor young scientists.

At ARMI, Currie will also continue his research program, focusing on zebra fish as models to study muscle disease and the molecular mechanisms underlying vertebrate embryonic patterning. This research offers clues to the treatment of human genetic diseases like muscular dystrophy.

ARMI will integrate research in three key platforms: structural biology (molecular level), cell biology (cell level) and regenerative biology (organism level). This work will form the basis of treatments for conditions such as neurodegenerative disorders, diabetes, arthritis, and musculo-skeletal and cardiovascular diseases.