HARD CELL - Stem cell
The days of faceless scientists working long hours for meagre salaries and little recognition are long gone. The link between the corporate world and the laboratory is well established - no more so than in the field of stem cell research. By ALAN DEANS
It took the imposing presence in Sydney last year of Superman's alter ego, Christopher Reeve, to change national laws and elicit large government grants that enabled the revolutionary stem-cell project of controversial medical researcher Professor Alan Trounson to fly. Much more than the legendary power of a comic book hero will be required, however, if the National Stem Cell Centre is to keep soaring.
The NSCC has grown in recent weeks from an infant state to one of adolescence. Yet serious hurdles make its success anything but a certainty. Something approaching $60m has been pledged in government and private research funding so that Trounson can pursue a dream: that stem cells from human embryos hold the key to life-saving treatments for crippling disorders, including diabetes, paralysis, osteoporosis and cardiovascular disease. This is a lot of cash in anyone's terms. However, even when mated with Australia's pre-eminent brains, it is unlikely to be enough.
The Bulletin has learnt that:
Cornerstone funding of $43.5m from the Australian Research Council and the Department of Industry, Science and Resources runs out within just three years. Initially, it was to be spread over five years, giving longer for scientists to strike commercial success.
The compressed timetable could pressure the NSCC to favour projects that return quick dollars. One such deal is under way to seek approval from drugs and medical devices regulator, the Therapeutic Goods Administration, to license existing American tissue repair technology.
The NSCC could also be forced into more deals with foreign research groups. This would challenge a key government criterion that it provide the "maximum benefit for the Australian economy and society". It is certain to disappoint many Australian researchers who are queueing at Trounson's door for money.
Despite the government writing unprecedentedly tough rules into the NSCC's funding deed, questions are being asked about the personal financial gains that could be made by senior executives. Trounson, for instance, owns shares in a private company that provides monkeys for medical research ? a commodity the NSCC has said it will require. During the funding approval process, he was pressured to sell, for reasons of conflict of interest, shares in a Singapore group that markets stem-cell lines. That company, ES Cell International, is a partner in the NSCC.
The appointment of Australian-born skin repair pioneer Dr Stephen Livesey, and a deal signed with the US company he co-founded, has raised issues of conflict over shares he owns in that company. Already, the NSCC collaboration seems to have boosted the stock of his New Jersey-based LifeCell Corp.
None of these issues is in themselves insurmountable. But they have resulted in the NSCC starting life very much on the back foot. It has had to weather a surprising and little-reported investigation ordered by Prime Minister John Howard into how it was awarded the government grants in the first place. The investigation included issues of probity, conflict of interest and arrangements for assessing the veracity of claims that were made on scientific matters. While given a clean slate, it resulted in the stricter funding agreement and the delay in start-up. The situation also provides potentially fertile grounds for opponents of Trounson and embryonic stem-cell research. Opposition came from across the political spectrum last year to a new law allowing human eggs left over from IVF treatment to be used to develop stem cells for research. The uniting forces were religious objections to the destruction of embryos and adherence to bans on genetic research. Some are privately warning that they will monitor developments as they unfold.
Trounson himself gives a blunt assessment of the NSCC's funding dilemma. "The government has given us a very important lift. [But] it's a huge ask to come up with meaningful results by June 2006. I am concerned about being able to demonstrate [success for the centre] inside of three years. It will take us some time to get going, around six months simply to select the projects that we fund. Then, we will have to look at our funding options down the track."
The NSCC wants to pursue four key areas of research. They are the use of embryonic and adult stem cells, both of which may lead to programs for cell and gene therapies. A third area is to combine cells and growth factors with a matrix structure that is derived from human skin. The aim is to repair damaged tissue, organs and bone. The fourth focus is on the use of stem cell therapies without triggering immune responses.
Trounson, however, has doubts about whether work will be pursued in all fields. He says that a review is underway, including into where the best research talent is concentrated and what intellectual property concerns exist. "We have to be very careful about making decisions. It is not possible to do everything. Everybody wants to be involved, but clearly there will be those who will be disappointed and those who will be rapt."
When the NSCC announced last year that it had beaten 28 applicants to become Australia's so-called Biotechnology Centre of Excellence, it named a long list of core scientific partners. They were Monash University, the University of Melbourne, the University of Adelaide, the University of Queensland, the University of NSW, the Peter MacCallum Cancer Institute, the National Centre for Advanced Cell Engineering, the John Curtin School of Medical Research, the Victor Chang Cardiac Research Institute and the Murdoch Institute. The idea was to increase the benefits by using more scientists at a large number of sites.
Despite this, foreign collaboration will be of key importance. Trounson and Monash University, a driving force behind the NSCC, have long had links in the US, Singapore and Israel. Trounson now says that global links will be critical to success. "We cannot be competitive in a worldwide movement unless we have supportive colleagues in other places."
One of the first decisions taken was with a US company that should boost the NSCC's coffers. Late last February, even before funding had been finalised, it was announced that LifeCell Corp director and chief scientific officer Livesey would head the key tissue regeneration area of research. He has since also been named as chief scientific officer.
Livesey is actually overseeing the granting of regulatory approval to sell LifeCell products in Australia. Any funds will accrue to the NSCC. His experience doing this in the US is to be put to further use to ensure that any Australian breakthroughs can quickly be brought to market. Livesey is also responsible for research into combining stem cells with LifeCell's proven tissue matrix technology. This may lead to groundbreaking developments, such as the growth of replacement organs in a laboratory for transplantation into needy patients.
The hiring of Livesey, while widely regarded as a coup, has had its troubles. He was the subject of intense negotiation with the federal government about managing the conflict of interest between his new role and his ongoing involvement with LifeCell. Of key significance, Livesey still owns 107,883 shares in LifeCell with a market value approaching $800,000.
Increasingly in research, conflicts arise involving the financial interests of individual scientists. Long gone are the days when they were expected to work for the good of mankind, collecting a nominal salary and remaining largely anonymous despite making big breakthroughs. That is mostly because governments, as the main financial backers, want discoveries to be quickly commercialised to generate the greatest benefit. The inevitable outcome is the forging of strong links between pure research and business.
According to Professor Wayne Hall, director of the office of public policy and ethics at the University of Queensland's Institute of Molecular Bioscience, there needs to be a balance between regulating such conflicts and getting the work done. "It has to be done in a way that retains public confidence and public trust. Information about conflict of interest and commercial relationships should be open to inspection by an independent group or body as a type of audit function. As a general rule, if people are in senior positions it would be preferable that they do not have conflicts of interest, particularly personal financial interests."
Clearly, factors such as Hall cites were in Howard's mind last year when he commissioned the Allen Consulting Group to review the selection process leading up to the NSCC funding. Allen detailed a number of conflicts between the government's panel of experts, appointed to select the best bid, and the bidders themselves. Four panel members were excluded from some discussions, and one ? CSIRO chief executive Dr Geoff Garrett ? had to resign because the CSIRO was involved with a bidder.
Allen Consulting concluded that while it was satisfied with the "high levels of integrity and thoroughness" of the process, it was essential that efforts were made to institute best practice "in the areas of conflict of interest, adherence to ethical codes and transparency". It said that conformity to the code relating to conflict of interest should subject to periodic independent audit.
The exact details of how the government and the NSCC dealt with the Livesey matter and future conflicts under the funding deed, are being kept secret. A department of industry spokesman cited privacy and matters of commercial confidence for not allowing The Bulletin to view the documents. He did say, however, that an audit process could be undertaken by the auditor-general or Privacy Commissioner.
What has been agreed is that Livesey cannot be involved in any financial or business decisions that involve the NSCC and LifeCell, despite his senior role and close relationships. The centre's chief operating officer, Dianna deVore, says the solution was worked out with the government in a special agreement before Livesey was hired. It does not require him to sell his LifeCell shares, however.
Livesey denied to The Bulletin that he had already profited thanks to a sharp rise in LifeCell's share price since the NSCC deal was announced. He contended that the increase had occurred thanks to a deal LifeCell negotiated in June with another medical company, Stryker.
LifeCell did announce such a deal, but the NSCC arrangement was first disclosed more than three months earlier on February 28. The shares were then hovering at about $US2.50 each. They rose strongly between then and the Stryker deal being announced, trading at up to about $US3.75. They have since hit nearly $US6. While LifeCell is a pioneer in tissue regeneration, it is capitalised at only $165m and has just become profitable. Its Australian stem-cell deal, then, could be of significant benefit.
DeVore says that all senior staff in the NSCC have had to disclose any personal financial interest that may create a conflict. "If any other potential conflicts emerge, we will manage them ? it will be handled on a case by case basis," she says.
One such problem could be Trounson's shareholding in Maccine, a company established with Monash University to source monkeys from Indonesia for medical research. Science magazine reported in June 2002 that NSCC researchers "anticipate a collaboration" with Maccine. Trounson is quoted in the publication saying he hopes to use animals at Maccine's primate centre to test potential therapies involving blood, skin, cardiac muscle, lung, liver and brain cells.
Asked if he had any remaining financial interests that might conflict with his NSCC work, Trounson at first said that he "did not honestly see any". But when reminded about Maccine, he agreed that his investment could ? "one day" ? become a conflict. "If that is the case, I would not be involved in any business with that." If required, Trounson said that he would sell shares that he holds to get rid of any conflict that arose.
While conceding that he hopes his opponents will find something else to focus upon, Trounson knows that this is unlikely. During the often heated selection process last year, he was quizzed closely on his part-ownership of stem-cell researcher ES Cell International. He was also forced into making two embarrassing backdowns over claims about the potential of stem cell therapies.
One was that embryonic cells were used to treat paralysis in an experiment with rats ? shown on a video ? when in fact it was germ cells. Another was that a research paper on the direction of embryonic cells into neural and motor neuron cells had been published by the prestigious Nature magazine, when it had been rejected.
These oversights simply stir up some traditionalists in the medical field, who charge that Trounson has pulled political strings and campaigned publicly to advance his research ambitions. They argue that the age-old path of peer review remains best. At the end of the day, only the results will tell.
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