Introducing cells to suicide
by Jane Tolerton | NZ Listener

A breakthrough strawberry-birthmark treatment discovered by a New Zealand surgeon and his team points the way to treatments for other tumours.

Swee Tan is a master of the rhetorical question. Outlining how his research into strawberry birthmarks could lead to a new way of treating cancer, he asks: “Would that be a good thing?” Suggest he could be making big money in cosmetic surgery overseas, and he asks, ‘Would I be a happy man?”

Hutt Hospital’s director of surgery should be happy enough – because what began as his research into disfiguring strawberry birthmarks has just won his four-strong research team a major international science prize. The implications for cancer treatment and regenerative medicine are so valuable that news of the award has been under wraps for a couple of months while the intellectual property involved has been registered internationally.

But the prize Professor Tan really has his eye on is a national research institute he plans at Hutt Hospital, being named after the two great pioneers of plastic surgery, New Zealanders Sir Harold Gillies and Sir Archibald McIndoe. That Tan and his team have done their breakthrough research without such facilities and with little funding is testimony to their dedication – and their willingness to spend huge amounts of time working for free.

Strawberry birthmarks grow from nothing into tumours that often cover much of the face within a year – and then shrink over about a decade. The usual strategy then, in the absence of an easy, effective treatment, was “just sit and wait”.

In one in 10 cases doctors had to intervene as a birthmark moved to cover an eye or obstruct the windpipe, threatening death by asphyxiation. High-dose steroids were the first line of attack. “This is a terrible thing to do to young children,” Tan says. “It’s like using a machine gun – and it doesn’t necessarily work. In 30% of cases the birthmark shrinks dramatically, and in 40% it stops growing – but in 30% it just keeps growing. When we got desperate, we used to use daily injections of interferon – with the side effect, in one in four children, of spastic in the legs. Because of that, people moved to chemotherapy. Treating a birthmark with chemotherapy – you have to be pretty desperate.”

That moment in April when Tan’s team won the John Mulliken Prize for the best science paper at the conference of the International Society for the study of vascular anomalies amazed their international colleagues. But Tan must be getting used to being considered amazing. Vicki Lee, the CEO of Cure Kids (formerly the Child Health Research Foundation), calls him “a cross between a genius and a saint”. The Museum of Wellington has made him a Living Treasure. Nicholas, a patient who blogged about his operation and recovery declared, “Swee Tan is part Chinese, part New Zealand and part Jedi.”

Tan has a gentle charisma. But within the velvet glove of charm, the iron fist of determination is clearly evident. His wife, Sanchia, says people once told him he could never be a surgeon with his hands, roughened by hard physical work as a child.

One of 14, he was born in a little village in Malaysia. “As children, we worked in the plantations – coconut, coffee, palm oil. Life was always a struggle, but I wanted to rise above that and have a professional life, and being a doctor was my dream.”

His father had only primary-school education, his mother none. They sent Tan to a Chinese school – “which means you can’t go anywhere, not even to the local university. It was madness, but they believed they should keep the heritage. In order to go to a Western country, I had to learn English. So after high school, I went to a college run by Australians in Kuala Lumpur for nine months. The way I learnt English was to read the newspaper from page one to the last page every day. But if you want to go somewhere, that’s what you’ve got to do. You can feel sorry for yourself and do nothing or get up and do something useful – and look beyond what you’ve got.”

Australia was offering free tuition to a limited number of students from developing countries, and having gained a place Tan started at the University of Melbourne’s Medical School in 1980. He got up at 5.00am three times a week to clean a supermarket. “In my final year the surgical registrar took me aside and said, ‘I don’t think it’s good for you to be half an hour late every morning’, and I had to tell him. He said, ‘Why don’t you take out a loan, and I’ll be the guarantor.’ He took that risk with me and gave me a hand. This is something I never forget and I do for the next generation – because it is the right thing to do.”

By then he had already experienced life across the Tasman. In their fifth year students could do an elective anywhere in the world, “so I came to New Zealand – and fell in love with this country. People here are so friendly, just so accepting, interested in you, not pretentious – and they are colour-blind.”

In 1987, having worked for a year in Melbourne Hospital, where he met Sanchia, then training as a nurse, he had to leave Australia under the terms of his scholarship. He took a job at Waikato Hospital, and Sanchia joined him after graduating.

“My first run was plastic surgery, which I knew nothing about. I was fascinated by the life-transforming nature of plastic surgery – and the creativity. You had a problem and you had to work out a solution. There’s no doubt people who want to do plastic surgery are naturally quite creative people, but no doubt that plastic surgery gives people the opportunity to be creative. It’s kind of a mutual attraction. Why did it attract me? It was the fascination when you see something happen – ‘Wow, I’d like to do that. It is an adventure.’”

There were only four positions in plastic surgery for training every three years. “It was almost laughable – mad! So, give it a go – and again people gave me a hand,” says Tan.

After two years at Burwood Hospital, he arrived at Hutt, where he qualified as a plastic surgeon and Sanchia had the first of their three children, now aged 17, 15 and 11. He won a fellowship to Oxford to do further training in craniofacial surgery – “you cut out eye sockets and move them, basically” – and to Harvard Medical School to do research. It was his boss there – John Mulliken, the man for whom the prize is named – who got him interested in strawberry birthmarks, or haemangioma.

“Life unfolds as you go along, not as you expect, and quite often much better than we expect. I believe in that. You have to take every opportunity and cherish everything that comes along. People often don’t realise opportunities at their doorsteps. It’s a matter of recognising them, because opportunities will keep coming and going – and they can just bypass you.”

When he arrived back in New Zealand in 1996 looking for a medical school post so he could get on with his strawberry-birthmark research, the only job on offer was one for just over half time in the Wellington Regional Plastic, Maxillofacial and Burns Unit. Based at Hutt Hospital, it now treats 12,000 people a year in the Central Region, stretching to Wairoa and taking in Nelson and Marlborough.

Tan was delighted to return to Hutt because he liked the culture – “very open, informal and unpretentious. If you had ideas, people would listen.”

He did have ideas, and he enrolled to do a part-time PhD with Otago Medical School to explore them. One was that there had to be a better treatment for children with strawberry birthmarks. But the big idea, even then, was that these birthmarks would give clues to dealing with other tumours, including cancer.

“It was clear to me where I should be investing my time – and that was going into the lab and understanding the mechanisms regulating the growth and remission of strawberry birthmarks.” To fund this research he also set up a private practice – doing cosmetic as well as reconstructive surgery. And he begged time in laboratories around the country in which to do his work.

“What was fascinating to me is that the growth and remission of the strawberry birthmark would involve a lot of cell multiplication and then cell death, and that therefore there must be mechanisms controlling that,” he says.

In 2000 Tan discovered the gene responsible for the regression of strawberry birthmarks, and shortly afterwards he and Wellington School of Medicine senior scientist Dr Paul Davis discovered the gene involved in their growth. But Tan’s most significant discovery was the origin of strawberry birthmarks – stem cells – and the way these cells are controlled.

“In the body, you’ve got the Renin-Angiotensin system. This system has been known for centuries, but it’s only been known to regulate blood pressure,” he explains. “What we’ve discovered is that the Renin-Angiotensin system is a vital mechanism controlling these stem cells. Now we’ve found you can use a beta blocker, Propranalol, which is usually used for treating high blood pressure, to treat strawberry birthmarks by blocking renin to stop cell multiplication – which causes them to commit suicide.

“So now we’ve got a very simple treatment. If a child is three months old, the strawberry birthmark is expected to grow three times as big by age one. We treat them with a beta blocker, and it is shrunk in three days and gone three months later. So just think about this concept of fighting a tumour with an anti-hypertensive drug – to manipulate the Renin-Angiotensin system – instead of using chemotherapy. This is why I say we will be called heretics. This is a brand new concept. We believe this research will set the scene for research for the next 60-100 years. It is completely different from what people have been pursuing for the past 60 years. We are talking about treating the tumour without trying to kill the cells – you just make them commit suicide.”

The discovery has an obvious implication for treating cancer, but there are others. “The wider implication comes from knowing the roadmap to the mechanisms that control embryonic development – and therefore tissue regeneration and cancer growth. We believe we know that roadmap, and at least one of the control mechanisms. Because of this we are able to grow red blood cells and bone tissue and fat tissue from the stem cells we take from strawberry birthmarks. Potentially, we could use these cells for bone marrow transplant in leukaemia treatment. We could grow blood vessels across a blockage in a coronary artery or a diabetic foot. We could replace a piece of missing bone, in situ.”

It was the research on the Renin-Angiotensin system and strawberry birthmarks that won the international science prize for Tan and his team – Darren Day and PhD student Tinte Itinteang from Victoria University’s School of Biomedical Sciences, where the lab work is done, and Hutt Hospital pathologist Helen Brasch.

Itinteang – from Kiribati via scholarships to St Patrick’s College, Silverstream and the University of Melbourne Medical School – was supposed to present that paper in Belgium. But as volcanic ash spread over Europe, the New Zealanders were told to go to Montreal and give their seven papers via video conference. As it was too late for Itinteang to get a visa for Canada, Day presented the winning paper. The response of their international colleagues went two ways, says Day. “Every one was going, ‘It’s so obvious! Why didn’t we think of it?’ But there was also a feeling of, ‘Who are these people from New Zealand, and what would they know about it?’”

The team did not want to patent their research. They wanted everyone to be able to use it. But a patent attorney advised them against this approach – telling them that if they didn’t, someone else would.

So the Gillies McIndoe Research Institute now holds the patents for what is termed a series of “inventions” – even though the institute doesn’t exist yet in terms of bricks and mortar. The first significant move towards putting the institute on the drawing board came in 1998 when Tan’s old boss at Oxford asked if his top student could help with the research – and Tan had to turn him down because it was unpaid.

Tan hatched a plan. “One evening I invited some people to my house to dinner. After some wine they got really happy and I said, ‘I’ve got this idea – a charitable trust to raise money and invest it, and then we can carry on the research.’”

Those guests and their host formed the Reconstructive Plastic Surgery Research Foundation to fund a research fellow position.

Then, in 2000, when Tan was about to have three months off to write up his PhD thesis, the director of plastic surgery at Hutt Hospital, Dr Max Lovie, suddenly died after 30 years in the job, and Tan was asked to run the unit. “I thought, ‘Where shall I invest my time?’ It was an easy thing for me to give away cosmetic surgery.” He has kept just half a day a week of private practice.

When Tan was persuading his guests to set up the research foundation, he deliberately presented only part of his plan. “I knew, having worked in med school, that if I really want to make a difference, I needed a lab dedicated to this.”

He kept putting “research institute” on the agenda, and finally the board backed it. With the aim of making it a national, rather than regional, institution, that board now has members from the country’s other plastic surgery units in Christchurch, Hamilton and Auckland.

The Gillies McIndoe Research Institute for Reconstructive Plastic Surgery was formally launched in May 2009. But what was actually launched was a fundraising effort – $3.5 million to set up six laboratories in the empty ward above the plastic surgery unit at Hutt Hospital, and then $10 million for an endowment fund to keep them running.

Tan notes that the Hutt Valley District Health Board’s business is patient care, not research. But it has supported the research and is happy to host the institute – a most uncommon feature for a New Zealand public hospital. He is wedded to the public health system. “I think I am a born socialist,” he declares, “but with one caveat. I believe everyone should be equal as long as the level is high, not low – as long as everyone is able to drive a Mercedes-Benz.”

His professorship is from the University of Otago’s Wellington School of Medicine, which has set up a chair of plastic surgery at the Gillies McIndoe Research Institute – and appointed him to it. Cure Kids is raising money to fund the chair in perpetuity, and has got about $1 million so far. But the fundraising effort to fit out the ward with laboratories has yielded less than $1 million, some of it just in kind or pledges.

The only time Tan looks other than completely relaxed and confident is when he talks about his fundraising efforts. “I’m not good at saying, ‘Can you give?’” Hutt City Mayor David Ogden, who is also a member of the Hutt Valley District Health Board and is leading the institute’s fundraising campaign, likens Tan to a “gospel preacher” when he’s in front of an audience. He makes it sound spiritual – and good fun at the same time. However, “it is an adventure, a journey, with lots of ups and downs”, says Tan. “The money dries up, and you have to make the decision to carry on. You have to have that deep conviction that you are not going to give up. But it’s going to be hard. This whole thing is hard. Set up a research institution. Make something out of nothing. It is very ambitious. You want to be able to create tissue, to grow bone or a piece of cartilage or a tooth. That’s ambitious. People can call you mad, or they can call it exciting. I choose to believe it’s exciting. And it’s not just me, it’s a whole bunch of people – who do the work for free. None of this could have happened without team members believing in this common madness.”

That madness will become orthodoxy in a short time if Tan’s team keeps up its momentum. Last month, Day and Itinteang gave three presentations at the eighth annual meeting of the International Society for Stem Cell Research in San Francisco. Tan has been picked by the New Zealand Association of Plastic Surgeons to speak at the American Society of Plastic Surgeons conference in October.

“They wanted us to pick the best science paper,” says the New Zealand association’s president, Howard Klein. “There was no question it had to be Professor Tan, who is recognised internationally by his peers as doing the highest quality work in this area. He’s a treasure for everybody – an exceptional researcher, a good administrator, a wonderful teacher. He’s really the total package in terms of what you want as a surgeon – and he’s a lovely guy.”

Tan, a surgeon first and foremost, says it’s a privilege.

“I have the privilege to see the human spirit, the courage people have and the tenacity to get through all this. Some people have surgery, radiotherapy and even chemotherapy. But they come through the other side. And I think a lot are better people – much better people. They appreciate the compassion people have for them. They realise what the human being can do for other people, what they can do for themselves. And they also realise the unique opportunity everyone has being alive. I don’t have any science to prove it, but I think people are more drawn to earth, more human.”