Alan Trounson: On the right side of history

Alan Trounson has faced down a charging black rhino. It is not the worst confronation he has experienced during an eventful career.

In the 1980s Trounson transformed in vitro fertilisation (IVF) from a hit-or-miss procedure into the routine treatment that has brought some five million babies into the world.

In 1998 his team was one of the first to capture the immortal stem cells that exist so fleetingly in the developing human embryo. These pioneering technologies made Trounson the target of incensed Catholics, feminists, politicians and journalists. Trounson faced each onslaught, shrugged off the bruises and moved on to the next challenge.

There was no shortage of charging rhinos during his seven years as President of the California Institute of Regenerative Medicine (CIRM) – the world’s biggest, boldest push to enlist embryonic stem cells in the fight against human disease. When Trounson left the post last year to spend more time with his family in Australia, the report card was positive. An external review in 2012 found: “Overall, CIRM has done a remarkably good job.” Jonathan Thomas, chairman of CIRM’s board, praised him as “a remarkable leader” and “the driving force behind some truly innovative ideas”. “He brought the right personality skills; he made CIRM come alive and spread its wings,” offered Evan Snyder, a neuroscientist at the Sanford- Burnham Medical Research Institute.

Trounson is now back home. But at the age of 69, he is not contemplating the quiet life. The man whom colleagues describe as “a force of nature” and “with a sixth sense for sniffing the next breakthrough” is leaping into another challenge: harnessing the immune system to fight cancer. “I’ve had a fantastic time for the last seven years amongst the ‘can-do’ people of the world,” he says. “It’s infectious.”

So what’s the secret of this “force of nature”? Hard to say. Trounson is not given to introspection. “He doesn’t look back; he only sees green lights,” says Martin Pera, a long-time colleague and program leader of Stem Cells Australia. Trounson’s playwright daughter, Kylie Trounson, looked for answers in The Waiting Room, her recent play that delved into the maelstrom surrounding her childhood in the early days of IVF. Much of the play focuses on the anguish of infertile couples – the willing guinea pigs who became central players in IVF’s transformation from a 1980s experiment to today’s routine procedure. Schooled by Trounson in the fine points of human embryology, the couples encourage him to keep going despite failure after failure. “Were they selfless or selfish?” the playwright asks of the audience. And what of Trounson himself – selfless or selfish? The young Trounson’s (now ex) wife Sue and daughter Kylie barely see him – he spends his days and nights at Queen Victoria hospital, waiting for women to ovulate their single egg so that he might fertilise it in the test tube and nurture the embryo. The Trounson of the play is an endearing, absent-minded scientist – quintessentially of the Aussie kind with his easy-going, plain-speaking manner. There’s not a drop of pretension in him. Yes, it’s Trounson through the prism of a daughter’s love. But it’s a fair depiction.

You might search for more clues to the man by probing into his childhood. But you won’t find a youngster burning with ambition to solve the great problems of medicine. He tells me he was a pretty average student, with a huge passion for animals and was “always going to be on the farm”. But he does share one telling anecdote. When he was about nine years old, his scout group was hiking in the Blue Mountains when a fire broke out. His team had already walked out but another was trapped. Some of the boys tried to outrun the fire up the mountain and died. Others ran down the valley back through the flames – and survived. “I thought that’s a pretty important lesson in life – that running away from something dangerous doesn’t really help. What you’ve got to do is figure out the best way to survive, and sometimes that’s running back into the fire.”

Trounson ended up solving the problem of women’s fertility after his own ambitions were hijacked. Like many Australian agricultural scientists of the 1970s, he was primarily concerned with the fertility of merino sheep. Their fine wool drove the nation’s economy, but while other breeds often gave birth to two lambs or more, merinos delivered only one. Trounson discovered that was because they ovulated a single egg. So he developed hormone treatments that increased the number of eggs released. He also learnt to fertilise eggs in the culture dish, split them and reimplant them into the sheep uterus to create twins or triplets.

Meanwhile, at Melbourne’s Queen Victoria hospital, flamboyant obstetrics professor Carl Wood was tackling the problem of women’s infertility in a not dissimilar way. His patients often presented with blocked fallopian tubes – the funnels that whisk an egg from the ovary to the uterus and where the rendezvous with sperm takes place.

Fertilising the egg in the culture dish and planting the embryo into the uterus would bypass the problem. But Wood had little success. When he heard about Trounson’s achievements, he drove out to the town of Jerilderie in rural New South Wales to recruit him. Ultimately he succeeded, although not until Trounson – who had become a rising star of animal embryo research – had done a stint at Cambridge learning how to multiply valuable cow embryos by splitting them and freezing them.

Wood’s team with Trounson in tow became phenomenally successful. They produced the third IVF baby in the world in 1980. But it was still a hit-or-miss procedure. Trounson then introduced the techniques he’d used in sheep, such as hormonal stimulation to trigger the ovulation of multiple eggs. He also kept the fertilised embryos growing in the test tube for several days to prove themselves, so that only the most robust could be selected for implantation. These methods revolutionised IVF’s success rate.

Today the procedure is so routine it may come as a surprise that the birth of IVF was controversial. Wood and Trounson were vilified in graffiti as “baby killers”. The charging rhinos they faced down included a strange mix of “right-to-lifers”, feminists and politicians.

The experience taught Trounson how to deal with confrontation. “You have to believe in yourself. And then have mentors like Carl Wood around who are pretty strong characters. They showed me that you could easily deal with it by just walking on.”

Perhaps, but not always. Trounson established a lab at Monash University to build on the IVF techniques he’d developed. They forged ahead with embryo freezing, so that women need not implant all their fertilised embryos at once and could avoid the risks of multiple pregnancies. They pioneered embryo biopsy techniques to identify embryos that might carry defective genes, and they learnt to give struggling sperm a helping hand by injecting them directly into the egg.

Then in 1995 this research was shut down by fiat of the state of Victoria’s Catholic health minister Marie Tehan. Even Nicholas Tonti-Filippini, a high-profile Catholic ethicist and vocal opponent of IVF, was appalled by the lack of democratic process. Many of the expert researchers from Trounson’s lab relocated overseas which is where these techniques were finally developed. All are now a routine part of the services offered by Australian IVF labs.

Trounson’s Monash lab switched focus to animal reproduction. A pet project was IVF for the endangered black rhino, which is how he came to be charged by one of them. While visiting a breeding park in South Africa, he sidled up to a sleeping hulk for a close-up shot when the camera’s automatic focus whirred and woke the beast. Trounson escaped narrowly thanks to the guide who let off a flare.

Research on human embryos had to move offshore. Trounson started collaborating with researchers at the University of Singapore. And then, some time in the early 1990s, his imagination was captured by embryonic stem cells.

Researchers had learnt how to cultivate these cells from mouse embryos. Like the embryo itself, they had the potential to form any tissue of the body. If the same cells could be cultivated from human embryos, the possibilities were dazzling. Once moulded into tissues and organs, they might provide spare body parts to replace those impaired by disease. Alternatively, model human tissues such as heart or liver, the ones most often damaged by drugs, could be used to test the safety of new compounds. But although researchers had tried for more than a decade, human embryos would not yield their stem cells.

Trounson recruited stem cell expert Pera from Oxford, who had trained Benjamin Reubinoff, an Israeli obstetrician on sabbatical in the lab. Reubinoff went to Singapore to work with human embryos and managed the feat. And so Trounson shot to fame once more. His team succeeded in isolating human embryonic stem cells in 1998, shortly after a group at the University of Wisconsin. But Trounson’s team had a possible strategic advantage. The US government, dominated by religious conservatives, had strangled funding for human embryonic stem cell research.

The challenge for Australia was to reap the rewards of the discovery. Trounson took to the hustings to convince the public and politicians. Embryonic stem cells would not only transform medicine, they could be the rocket to launch Australia’s sluggish biotech sector.

The rhinos charged. They included religious conservatives in the media and government, ethicists, feminists and many who simply felt unhappy about using human embryos in this way – even though surplus frozen embryos from IVF clinics, the proposed source of the embryonic stem cells, were being thrown into the garbage.

A tumultuous year followed. Trounson convinced the prime minister of the day, John Howard, that this was Australia’s chance to stake a major claim in pioneering research.

He won $45 million to establish a national centre of excellence for stem cell research. But before the centre’s work began, Trounson became the target of a smear campaign. The accusations ranged from assertions that he had misled politicians about the details of the science to conflicts of interest, all claims that were fully cleared by an independent investigation. Finally in December 2002, after a four-month delay, the Australian Stem Cell Centre (ASCC) was relaunched.

But it was no plain sailing. Seven different institutes were involved in the brave new centre, each with different ideas about what course it should chart. Should it be a voyage of discovery, or should they narrow the focus to developing one particular therapy?

It was a stormy environment and Trounson’s vision – closer to research than development – lost out. “History will show whether I got it right or wrong,” Trounson told me at the time. A year into the life of the ASCC, Trounson left. He started the Monash Immunology and Stem Cell Laboratories from scratch but had to compete for funding along with many other hopeful lab heads, some of whom were growing increasingly resentful that resources for stem cell research had been hijacked by the centre.

Was Trounson right about the ASCC? The centre certainly delivered excellent research and brought together multidisciplinary teams that pioneered the ability to grow the volumes of stem cells required for a clinical trial. Ultimately, however, striking the right balance between basic research, developing a therapeutic product, and keeping everyone happy was a tall order. The divisiveness in the leadership weakened the operation. The ASCC shut down in 2011 when it was unable to win further funding. By then Trounson had already moved on to far, far greener pastures. But that’s not to say it was any kind of pastoral scene.

Martin Pera shuddered when he heard Trounson was taking up the presidency of the California Institute of Regenerative Medicine. Pera had relocated to California in 2006 to become director of a stem cell research institute at the University of Southern California in Los Angeles. “There isn’t a day the CIRM leader doesn’t have someone angry with them,” he says. “From patient advocates to scientists, every time you make a decision, you brush someone the wrong way.”

Once again, Trounson was entering an inferno where science, politics and religion intersect. But this time there was an extra element to this combustible mix: an astronomic level of public expectation.

Three years earlier, Palo Alto real estate financier Robert Klein had convinced the citizens of California to spend $3 billion on stem cell research over a decade to usher in a new age of medicine. The US federal government had vetoed funds for embryonic stem cell research and a small group of politically savvy Californians decided it was time for people power. Some, such as Klein whose son has diabetes, had sick family members. In 2004, they mounted a successful ballot known as Proposition 71 to sell bonds to raise the money. However a legal push from the usual rhinos had stopped the funds by arguing that Proposition 71 was unconstitutional. Arnold Schwarzenegger, the governor who championed the initiative, helped with a loan until the courts overruled the objection. The bond money finally began to flow in late 2006.

CIRM was finally free to usher in the new age of regenerative medicine. It was not only a matter of spending money. California boasts some of the world’s best scientists – places such as the Salk Institute, Stanford, California Institute of Technology and the University of California are studded with Nobel Prize winners. But the pipeline for delivering cures that worked in the lab to the clinic had not been built. “Oh to be a rat”, quipped the late Christopher Reeve, the actor who played Superman and became paralysed after falling from a horse.

The obstacles faced by stem cell researchers had been clear for some time. To achieve the big goals, such as curing paralysis or diabetes, researchers must work together in a focused way, just as they did to put a man on the Moon or read the human genome. But the academic system was geared for competition, not collaboration. And then there was the “valley of death”. Taking a rat cure into clinical trials is extremely costly, and not something that is covered by research grants. On the other hand drug companies aren’t prepared to take a punt on laboratory research until early-stage human trials show promise. So many a promising rat cure never makes it across the chasm.

When it came to stem cells, the valley of death was wide indeed. Training stem cells to produce spare body parts was no easy matter. There were also huge concerns about the potential of stem cells to run amok and cause cancer. The well-established procedures for checking the safety and efficacy of new drugs did not yet exist for stem cells. By 2007, several stem cell companies had already come and gone, unwilling to wear the high level of risk. Even the pioneering company Geron, that had paved the path for trials on spinal cord injury, abandoned their efforts in 2011. Rising up in their place all over the world was a series of snake oil clinics, promising unproven stem cell therapies to desperate patients. CIRM would be the knight in shining armour galloping in to rescue the promise of stem cell therapy. “We have to be an instrument of change,” Trounson told Nature magazine in 2008. “Because if every single stem cell treatment costs $800 million, we’re just never going to get there.”

CIRM might or might not get people out of their wheelchairs but it would certainly get stem cell medicine out of its paralysis.

By the time Trounson arrived, the basic operation was underway. Twelve new buildings were going up, necessary because researchers could not carry out embryonic stem cell research in federally funded facilities. The research to be carried out in the new institutes was evaluated first by an expert panel of scientists from outside California. The winning proposals were then put to a 29-member board with an Orwellian title: the Independent Citizens’ Oversight Committee (ICOC). With the ICOC as the jury, Trounson was the presiding judge, charged with convincing them of the relative merit of the proposals. These hearings took place every two months – all under the intense gaze of the media.

If your mission is to spend $3 billion of public money wisely and deliver cures and biotech businesses in a short space of time, there is bound to be conflict. And there was. Trounson’s predecessor Zach Hall had quit. Then chief scientific officer Marie Csete left in 2009. In a replay of what Australia experienced with the ASCC, a major point of conflict was deciding where to focus efforts along the spectrum from basic to applied research.

The ICOC board members – scientists, patient advocates, business people, Hollywood representatives – had differing ideas. Achieving consensus was a formidable task. And the entire process was as transparent as a reality TV show, with a website dedicated to dissecting every wrinkle. Nevertheless they were able to agree on the funding of some 800 projects. “In the end I thought it was a useful way to run an organisation like that,” Trounson reflects.

Many have noted that Trounson’s easy-going Aussie personality was a helpful lubricant. “One of the key features of his extraordinary leadership was the seamless integration of patients, industry and researchers into a harmonious, synergistic union,” says Jeff Sheehy, a board member and an HIV patient advocate. “One thing’s for sure – Trounson learnt in a big way from his difficult experiences in Australia,” notes Pera.

Besides adjudicating the hearings, Trounson set about building crucial pieces of the medical product pipeline. At the early end, this included establishing a Genomics Centre to decode the unruliness of stem cells by reading their DNA. It was also a requirement that all the research findings had to be rapidly published, and any cell lines and materials made available for sharing.

Trounson also established Disease Teams – the middle section of the pipeline. They were composed of lab scientists, doctors and companies who joined forces to tackle a specific disease. “I’m proudest of those,” says Trounson. Like a biotech company, the teams had to meet draconian milestones every six months for funding to continue. They were overseen by the consummately experienced Ellen Feigal, who Trounson spirited away from her post as medical director for the biotech giant AMGEN. At the end of the pipeline were the Alpha Clinics, specialised to deal with the medical requirements of stem cell trials. Trounson says they were modelled on the first Australian IVF clinics.

CIRM also completed the path for stem cell clinical trials that Geron had started. The US Food and Drug Administration knew how to deal with stable drugs. But stem cells were quixotic. For each cell type, what tests were required to ensure the cells were stable, safe and of the right type to replace the diseased tissue? The criteria for cells to repair the spinal cord, for instance, would be different to those required to replace a failed pancreas.

At the time of writing, CIRM has 20 clinical trials at various points in the pipeline. They tackle a vast range of illnesses. Some use embryonic stem cells as spare parts. Trained to secrete insulin, they are being grafted into patients to treat type 1 diabetes, or as retinal pigmented epithelial cells to treat a form of blindness known as macular degeneration. Other trials use stem cells to find new drugs. For instance some types of cancer are driven by cancer stem cells that resist radiation and chemotherapy. By isolating these stem cells, researchers have developed new drugs to target leukaemia and breast cancer.

For many, this is a dazzling success story. Pera thinks back to the early 2000s in the Monash lab when they first managed to produce little patches of black cuboidal cells from embryonic stem cells – the same types of cells that his former lab in Southern California is now testing in the eyes of people with macular degeneration, thanks to CIRM. “Within five years, we had a clinical trial. I couldn’t see that happening anywhere else.”

Will the trials pay off in new treatments? It seems a premature question – most take closer to 20 years to develop. But CIRM must answer the question soon. After 10 years, the funders of Proposition 71 are getting restless for a return on their investment.

As for Trounson, his sights are fixed on importing CIRM’s can-do attitude back to Australia. Inspired by the success of new cancer treatments that mobilise a person’s immune system, he is gearing up to build a cancer “Disease Team” on his home turf. And he’s in a hurry: “I don’t have another 20 years.”

At least this time there shouldn’t be too many rhinos.

Also by Elizabeth Finkel: How Australia entered the stem cell race