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By The Hon. John Brumbyamanda.caples@iird.vic.gov.au

Australia has enjoyed a long period of sustained economic growth. However, unless we are pre-pared to follow through with a new wave of re-form, this prosperity cannot last. This is why in

2007 Victoria will put forward to the Council of Aus-tralian Governments (COAG) a National Innovation Agenda to tackle emerging challenges to build a strong future for ourselves and for generations to come.

It is this view of the future, and the need to invest today in the treatments of tomorrow, that has led Victo-ria to take a lead in the national debate on an improved regulatory environment for stem-cell research. It has not been an easy road: just six months ago the outcome was far from certain, with the Prime Minister proposing to shelve the Lockhart Report and its recommendations, apart from those of a purely administrative nature.

It is instructive to go back to the beginning to understand how we have reached the position today where the Patterson Bill allowing Somatic Cell Nuclear

Transfer (SCNT) has been passed by both houses of Parliament. In 2002, COAG agreed to a nationally consistent legislative framework that banned all forms of human cloning (including SCNT or ‘therapeutic cloning’), and allowed research on excess human em-bryos from IVF clinics, including for stem-cell research, within a strict regulatory regime. An intergovernmen-tal agreement was established to ensure a consistent ap-proach. The Commonwealth enacted the Prohibition of Human Cloning Act 2002 and Research Involving Human Embryos Act 2002 (‘the Acts’), and mirroring legislation was put in place by the states.

As required by legislation, the Lockhart Commit-tee was commissioned in 2005 to review the Acts. The Victorian Government was actively involved in the consultation process. In 2005 we made a significant contribution to the Lockhart Review with two written submissions, my presentation during the public hear-ings and a private meeting between the Victorian Pre-mier and the Lockhart Committee.

We did this for two reasons. First, because the Victorian Government believes we need to develop knowledge-driven, high-skilled industry sectors where

Victoria’s contribution to the stem-cell debate

In THIs Issue: Contributors discuss stem-cell technology; our new President presents his challenge for the Fellowship; and the interplay of food, water and phosphate is addressed

Number 144 AustrAliAN AcAdemy of techNologicAl scieNces ANd eNgiNeeriNg (Atse)mArch 2007

u Page 2

Atse is an independent body of eminent Australian engineers and scientists established to promote the application of scientific and engineering knowledge to practical purposes. Focus is produced to serve this goal.

opinions expressed in this publication are those of the authors, and do not necessarily reflect the views of Atse. material published in Focus may be reproduced provided appropriate acknowledgement is given to the author and the Academy.

Honorary editor: dr d c gibson ftse Technical Consultant: dr Vaughan beck ftse

ausTralIan aCademy oF TeCHnologICal sCIenCes and engIneerIng (aTse)address: ian mclennan house, 197 royal Parade, Parkville Vic 3052Postal address: Po box 355, Parkville Vic 3052Telephone: 03 9340 1200 Facsimile: 03 9347 8237 email: editor@atse.org.auAcN 008 520 394 AbN 58 008 520 394Print Post Publication No 341403/0025 issN 1326-8708Focus design and production: www.coretext.com.au

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we have sustainable and internationally competitive advantages. Medical research and biotechnology is one such sector, and the Victorian Government has backed it through its $1.8 billion Innovation Agenda and an ambitious target to position Victoria as a top-five life sciences location globally by 2010.

Individual examples of progress abound, but per-haps the best single indicator of progress is that, for the first time, Melbourne joined London and Boston as one of only three cities in the world with two biomedi-cal universities in the top 20 according to the 2006 Times Higher Education Report.

Our second reason for advocating the liberalisation of stem-cell research laws was because we have a respon-sibility as custodians of nearly a century of medical re-search excellence that has contributed so much to the delivery of better health outcomes for the nation – the colony-stimulating factors and Relenza being just two examples. As we saw the situation, we had a choice to make: to embrace, or not, amendments to legislation that will allow our scientists to contribute to greater knowledge and understanding of disease in an account-able and transparent regulatory framework, similar to that which has been successfully applied in the UK.

The Victorian Government believes that we should not impede progress that could alleviate the burden of disease on society and the family. The Lockhart Report, tabled on 19 December 2005, supported the Victorian Government’s three key recommendations to:¢ �maintain the ban on human reproductive cloning;¢ �update the legislation to allow for “therapeutic

cloning” (SCNT) – for the creation of disease-specific stem cells and patient-tailored stem cells; and

¢ �uphold the current rigorous national regulatory regime.COAG considered the Lockhart Report in July

2006. The Commonwealth indicated support only for administrative changes, thereby maintaining the ban on SCNT. In response, Victoria and Queensland reserved the right to consider state-based legislation to allow for SCNT as far as possible within their jurisdiction.

The Lockhart Report has widely been acknowl-edged as a comprehensive and balanced report – a view that the Victorian Government shares. But opponents to embryonic stem-cell research questioned the find-ings and the recommendations of the Review. Their arguments fell into three categories:¢ �opposition based on fundamental philosophical

and religious grounds;¢ �opposition based on the potential for exploitation

t From Page 1

cover story: stem-cell technology

from the editorA rt is the essence of all great design. Art is the magical blend of function

and form that makes a practical object beautiful. the earliest sketches of utzon’s billowing sails were art. the transformation and solidification of that beauty into the sydney opera house is a 20th century example of adventurous architectural and engineering art.

material matters were never the only concern of artists or designers. Automobiles and aeroplanes – probably the summit of engineering art for the layman – have never captured the mind as completely as the beauty of the human form and the fashions that clothe and adorn it. then there is nature and the intricate wing motion of a large bird thrusting upwards in flight. What aeroplane designer does not stare in wonder at the complex interplay of flaps and spoilers, lift and drag, incidence and yaw, that nature endowed long before man could calculate their use or measure their value.

Now there is assisted reproductive technology (Art). the rapid development of Art since the 1990s has raised ethical issues about what forms of human reproduction may be possible and acceptable, and about what uses of human embryos should be permitted for research purposes. governments and communities around the world have grappled with the ethical dilemmas that Art presents. Appointed by the minister responsible for human cloning and stem-cell research in June 2005, the lockhart committee consulted widely, reviewed existing legislation and made recommendations for change in december 2005.

issues the committee addressed included questions such as: when does human life begin? how far should society allow research involving human embryos? What safeguards should surround the research? should human embryos be accorded the same rights as human beings after birth? how should ‘human embryo’ be defined? What are the limits of in-vitro fertilisation (iVf), and related Art methods and human embryo research?

in looking for common ground, the lockhart committee found strong community support for medical research to help people who suffer from debilitating or incurable disease and conditions, through better understanding of the processes of disease and the development of new treatments. there is also considerable community support for medical research to help people have children, including a general acceptance that this process involves the ‘wastage’ of some embryos.

for some people, the values attached to treating disease and overcoming infertility are more important than the value of an embryo. for others, the value of an embryo, as a potential human being, is predominant.

A bill to implement the lockhart committee’s recommendations was passed by the senate in November 2006 and by the house of representatives in december 2006. contributors to this issue of Focus explore the strengths, weaknesses, opportunities and threats that Art brings to mankind. Will this Art be beautiful too?

ATSE Focus responds to feedback from its readers, both positive and negative. Opinion pieces of between 800 and ��00 words on topics of national importance will be welcomed. Please address commentary, topics for examination and articles for publication by email to editor@atse.org.au , or by mail to The Editor at Academy Headquarters. Electronic communication is preferred.

aTse office Bearers and executivePresIdenT Professor robin Batterham ao Faa

president@atse.org.auVICe PresIdenTs mr P J laver am viceprespjl@atse.org.au;

dr John nutt am vicepresjgn@atse.org.au Honorary seCreTary Professor Fred smith am

honsec@atse.org.auHonorary Treasurer mr Keith daniel

hontres@atse.org.auCeo mr John grace johng@atse.org.au

deadlines 2007-08deadlines for the receipt of copy for forthcoming issues of focus are:

11 may 200710 August 20079 November 200715 february 2008

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of women in the collection of eggs; and¢ �opposition based on the contention that no

progress has been made in the field to warrant a change in legislation.In my submission to the Senate Inquiry, I focused

on a response to these three points.

Community views and previous debatesAll groups – for and against – have a right to be heard in any debate. The question we considered was whether the views of the opponents to change were representa-tive of the broader community. The Victorian Govern-ment’s view is that they were not.

Opponents argued that community surveys were of limited value because the questions were phrased to lead the response. However, this criticism cannot be levelled at the June 2006 Roy Morgan poll in response to the question: “Scientists can now make embryonic stem cells for medical research by merging an unferti-lised egg with a skin cell. In this case, no fertilisation takes place and there is no merger of the egg and sperm. Knowing this, do you favour or oppose embryonic stem-cell research?”

The poll found that an overwhelming 80 per cent favoured embryonic stem-cell research by merging an unfertilised egg with a skin cell. Only 11 per cent were opposed and nine per cent were undecided. Similar lev-els of community support have also been expressed in the US, where there has also been recent intense debate over federal government funding for stem-cell research.

A keynote speaker at the Victorian Scientific Lead-ers Forum on Stem-Cell Research, held in Melbourne in October 2006, was Robert Klein, chairman of the In-dependent Citizens’ Oversight Committee of the Cali-fornia Institute for Regenerative Medicine. Mr Klein pointed out that California’s recent Proposition 71 to issue $3 billion in bonds to support stem-cell research enjoyed widespread support from voters despite tight economic conditions.

The reason for this support in Australia and in California is simple: most people recognise that stem-cell research can offer potential treatments to our most feared and damaging diseases.

exploitation of womenConcern about the exploitation of women is not new. The Australian community faced the issue in the 1970s with the emergence of IVF technology. Governments around Australia responded with legislation and regula-tion, which has led to IVF being an accepted part of our lives today. The IVF experience should give the Austral-

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ian public comfort that we as legislators are able to con-struct an acceptable regulatory framework to support the adoption of emerging scientific technologies.

The Lockhart Review recommends strict regula-tions relating to donor egg collection, which we believe balance the need to protect women from exploitation, with a way forward to provide women with the right to donate eggs if they wish.

Technical advances – the gough reportFinally, opponents to change questioned the progress made in the field of embryonic stem-cell research. Their contention was simple: opponents argued that because, in their view, there had been no progress in the field, it follows that there is no justification to change the legisla-tive framework. Setting aside the fact that it is difficult to make substantial progress in an activity that is banned, the contention was simply not true. However, sadly much of the progress was occurring internationally.

The Victorian Government accepted that the Lock-hart Review undertook a thorough analysis of the field in the preparation of their report. Notwithstanding, we felt it was important to take a closer look at the science. To do this the Victorian Government commissioned a sci-entific review of progress in the embryonic stem-cell field by an eminent molecular biologist, Dr Nicholas Gough, who – among a variety of other accomplishments – is one of the inventors of GM-CSF, which brings relief to cancer patients around the world on a daily basis.

The Gough Report represents a very thorough re-view of the peer-reviewed, published scientific reports in the field of embryonic stem-cell research, and is sum-marised elsewhere (on page 17) of this edition of Focus. Suffice to say here that the implications of the report are:¢ �that stem-cell technology is gaining (not losing)

widespread support across the globe;¢ �that the technology is moving rapidly to the point

where it could meet regulatory requirements for patient treatment;

¢ �that the SCNT process can produce competent cells;

¢ �that proof-of-concept is now available that SCNT can produce the desired functional outcome; and

¢ �that one of the greatest barriers to stem-cell therapy – tissue rejection – can be overcome by SCNT techniques.The Gough Report was subsequently endorsed by

Victoria’s Chief Scientists, Sir Gus Nossal and Profes-sor Graham Mitchell, who describe the progress made over the past four years with human embryonic stem-

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is to be expected for such a new field.We believe that the faith-based objections should

be respected, but that they do not represent the broader Australian community view. We believe that the IVF experience has given the Australian community every reason to expect us as legislators to develop, implement and monitor a regulatory framework that protects the rights of women.

Finally, notwithstanding the time it takes for medi-cal research to be adopted into everyday clinical practice, we believe that substantial technical progress has been made to warrant a change in legislation. This progress is all the more significant given the diverse regulatory environments around the world that this field faces. If progress in the field warrants further amendments in the legislation, then this will need to be justified in the nor-mal way. This is how a democratic process should work.

The Victorian Government is proud of its role in ad-vocating amendments to legislation that will allow our scientists to contribute to greater knowledge and under-standing of disease in an appropriate and transparent regulatory framework. We will continue to support har-monisation of the legislation through the COAG process and seek to champion a National Innovation Agenda to ensure the prosperity of Australia’s future generations.

JOHn BrumBy mP is the Treasurer of Victoria, minister for regional and rural Development and minister for Innovation in the Victorian Government. mr Brumby is the longest serving of Australia’s state treasurers. As Treasurer, he is responsible for the financial management of Victoria’s $�� billion budget sector, which represents more than �� per cent of the state economy. In February �00�, mr Brumby was appointed Victoria’s first minister for Innovation. He actively promotes innovative, creative and knowledge-intensive industries such as biotechnology, environmental technologies and advanced manufacturing.

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cell lines as “breathtaking” and foreshadow revolution-ary health benefits for the entire community.

Importantly, it was this report that I tabled on behalf of the Victorian Government at the Senate Committee hearing held in Melbourne last October. The Gough Report provided much-needed clarity on the advances in embryonic stem-cell research and SCNT and the timeliness of regulatory reform to enable that progress to continue. This report, coupled with expert advice from a number of witnesses, assisted the Committee to recommend proceeding with the Patterson Bill.

stem-cell forum and communiquéUpon receiving this new scientific evidence and the call for SCNT from our Chief Scientists, the Victorian Government convened a Scientific Leaders Forum on Stem-Cell Research to discuss the Gough Report and to hear from the deputy chair of the Lockhart Review, Professor Loane Skene.

What the Victorian Government wanted to achieve from this forum was an understanding of the require-ments and priorities in moving forward. The forum, chaired by former Australian of the Year and Victorian Chief Scientist Sir Gus Nossal, included many of Aus-tralia’s leading stem-cell and life-sciences researchers.

Following the forum, a communiqué was released that calls for continuation of the ban on human repro-ductive cloning and support for regulatory change as reflected in the Patterson Bill.

Victoria’s positionIt is just over one year since the Lockhart Report was tabled in Federal Parliament. In that time it has drawn a great deal of support as well as some criticism, which

legIslaTIon ImPlemenTs mosT reCommendaTIons

By loane skenel.skene@unimelb.edu.au

Late last year, both houses of Federal Parliament passed legislation to implement most of the rec-ommendations of the Lockhart Committee (the Legislation Review Committee for the Review

of the Prohibition of Human Cloning Act 2002 and the Research Involving Human Embryos Act 2002).

The new legislation will:¢ ��retain a national focus, with a federal licensing

body monitoring embryo research and reporting

to the Federal Parliament;¢ �continue criminal liability for widely condemned

practices, such as cloning to breed identical people or human-animal hybrids, and selling human sperm, eggs and embryos;

¢ �prohibit the creation of human embryos for research by fertilising a human egg with human sperm (except to the point of fertilisation for fertility research);

¢ �continue to allow couples in fertility treatment programs to donate embryos they do not need for use in research, instead of them being discarded. As before, that research will be permitted only under licence, with clear and transparent reporting processes so that the community can be

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assured that the research is justified and properly monitored. Also, a national stem-cell bank and a register of donated embryos will be established so that the number of embryos that are used in research will be minimised;

¢ �allow research on impaired embryos created in fertility programs (these embryos would previously have been discarded); and

¢ ��allow scientists to create human embryos for research by somatic cell nuclear transfer (the insertion of a person’s body cell into an egg that has had its nucleus removed). This research will be regulated by licence in the same way as research on surplus or impaired embryos created in fertility programs. The amendments will allow scientists to do three

new types of research. First, they will be able to fer-tilise human eggs and observe their development until the process of fertilisation is complete. Under earlier legislation they had to stop all research on eggs in the process of fertilisation before it was complete. The new endpoint will enable more information to be obtained to improve the success of fertility treatments and the training of staff in treatment programs. It will also help scientists to understand factors that impair early em-bryonic development and lead to genetic diseases.

Second, scientists will be able to do research on em-bryos created in fertility programs that are so ‘impaired’ that they are not fit for implantation. Previously, these embryos had to be discarded and the only embryos that could be used in research were healthy ones that had been frozen for later use by a couple, but were not need-ed because they had completed their family or decided not to proceed with the treatment. The earlier legisla-tion required these ‘surplus’ embryos to be destroyed if they were not donated for research or to another cou-ple. Scientists need to study impaired embryos as well as healthy ones in order to learn more about the reasons for genetic disease and the way that drugs might help alleviate the symptoms.

Third, scientists will be able to use somatic cell nuclear transfer (SCNT) to create embryos that are ‘matched’ to particular people (the people whose body cells are used to create those embryos). In the short term, this will enable scientists to develop disease-spe-cific stem cells and models of disease to study the cause, progression, diagnosis and treatment of disease. In the future, it may be possible to treat genetic diseases, such as diabetes and Parkinson’s disease, or spinal injuries, by implanting stem cells developed from a person’s own tissue, which are less likely to be rejected than cells do-nated by another person.

The creation and destruction of human embryos for the purposes of research is very contentious, and the Lockhart Committee’s recommendations attracted widespread debate. Some critics argued that human embryos have a special moral status and that it is mor-ally abhorrent to create and destroy them for research. Others said that allowing SCNT will inevitably lead to reproductive cloning (the creation of a duplicate per-son), and that embryonic stem-cell research is unneces-sary or ill-founded as it has produced no new insights or therapies and can be done using adult stem cells.

However, the Lockhart Committee concluded, af-ter lengthy community consultation and careful delib-eration, that SCNT should be allowed because of the potential benefits of the research. Not all communities in Australia attach the same significance to the embryo. Other concerns, such as the need to care for the sick and vulnerable and respect the wishes of individuals, are also morally important, and the community, legal system and government already allow donated embryos to be used in research.

The committee distinguished the creation of em-bryos by SCNT from the creation of ‘sperm-egg’ em-bryos. An embryo formed by SCNT is not formed from a human egg and sperm, but from an egg and a body cell. Embryos created in this way have a different moral status from those formed from an egg and a sperm by a couple trying to have a baby. Where an embryo is formed to produce stem cells compatible with the person whose body cell is used, this is more akin to growing skin cells for a skin graft than to having a baby, and there are fewer objections to creating an embryo for the purpose of us-ing its cells in research and treatment. (The committee said that an embryo created from an egg and sperm for research should not be used to extract stem cells but only to improve fertility treatment. Also, such embryos must not be allowed to develop beyond the time when the embryo is first formed. That is, the research must stop as soon as the egg has been fertilised.)

Allowing SCNT under licence will not inevitably lead to reproductive cloning. The Australian commu-nity almost unanimously opposes it, and it should re-

‘ Not all communities in Australia attach the same significance to the embryo’

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THe lIne BeTween exPloITaTIon and HoPe

By megan munsiemegan.munsie@stemcellcentre.edu.au

When the late Justice John Lockhart, chair-man of the Commonwealth Legislative Review Committee looking at the use of human embryos in research, met with sci-

entists at the Australian Stem Cell Centre in October 2005, he was very quick to ask what was being done to manage the expectations of the public, particularly pa-tients, with respect to stem-cell research.

Justice Lockhart clearly expressed his desire to see scientists take significant responsibility for ensuring the hopes of patients watching stem-cell research with very high expectations were not exploited, and that infor-mation released into the public arena was accurate and intelligible to the average Australian. His comments did not just apply to scientists undertaking embryonic stem-cell research, but to all scientists working across the stem-cell field.

Opponents of stem-cell research have often accused scientists of exploiting the hopes of patients to drive legislative change in their favour. Patient advocates heat-edly describe this claim as patronising and duplicitous. Many patients and their families actively follow scientific progress into their particular condition with the full un-derstanding that they may not directly benefit from the research; they may not be cured, but hope that research will aid the development of treatments for sufferers sometime in the future. This hope is shared by medical researchers, who are generally motivated by the desire

to improve the lot of people who may be suffering great hardship, and are often highly motivated by their own personal experience of specific diseases. The ultimate reason scientists do what they do is most commonly to ‘make a difference’.

Scientists undoubtedly need the practical input of patients in the course of their work as donors of cells for the necessary basic research, and ultimately as recipients in clinical trials of any new treatment. Patients and their families want to be informed of new discoveries and have these discoveries put in context – something that is not always clear from media coverage, which often equates a breakthrough with a cure.

Patients and patient-support groups have an impor-tant role to play in any medical science development. The debate in regard to the Patterson Bill is a recent example where patient groups have made a real contribution to discussion. Such groups have always played an active, if not a political, role. It can only be expected that their role will continue to increase. Scientists have a duty to provide them with objective and non-emotive informa-tion about developments in their field of interest. They should not shy away from telling them the good and bad news as part of a process of continual dialogue and dis-passionate discussion regarding developments. Scientists can only enhance the respect they garner from the com-munity if this done. Similarly, this approach is the appro-priate way for scientists to deal with those individuals or groups who actively oppose the developments, be it for political, religious, cultural or other reasons.

Looking specifically at the prospect of generating stem cells using the SCNT technology – also known as therapeutic cloning – there is a distinct possibility that participants could be exploited, and this must be dis-

main prohibited. However, the best safeguard against reproductive cloning is restricting the degree to which embryos can be matured, and prohibiting their implan-tation into women. It is reassuring that there have been no instances of non-compliance with legislative and regulatory requirements in Australia (where embryo research has been allowed under licence) or in the UK (where SCNT is allowed).

It is true that we do not know at present what ben-efits, if any, will come from human embryo research. However, that is true of many types of scientific research. Already, there have been promising results in animal tri-als that establish ‘proof of concept’ for treating medical conditions by implanting ‘matched’ stem cells.

The Lockhart Committee was fully aware of the dif-

ficulty of these issues. It struggled long and hard over its recommendations, taking account of more than 1000 written and oral submissions it received. Its final recom-mendations were based on the potential benefits of the research for infertile couples and people suffering from genetic conditions. Ultimately, the committee conclud-ed, on the basis of all the views presented, that it is hard to accept that research which may benefit many people should be prohibited because of religious or philosophi-cal objections from others, however sincerely held.

LOAnE SKEnE is Professor of Law at the university of melbourne. She was deputy chair of the Legislation review Committee for the review of the Prohibition of Human Cloning Act 2002 and the Research Involving Human Embryos Act 2002 (‘the Lockhart Committee’), of which she became spokesperson after the sudden death of Justice Lockhart in early �00�.

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cussed openly and prevented.The purpose of performing this type of research is to

generate ‘tailored’ stem-cell lines – stem-cell lines made from a patient’s own cells – that would potentially allow researchers to gain a better understanding of a particu-lar disease, or even generate cells for transplantation that would not be rejected by the patient. At present, SCNT is the most likely route to achieve this objective. Howev-er, the technique hinges on the use of human eggs – spe-cifically, the cytoplasm of the egg – to provide the neces-sary factors and mechanisms to transform the patient’s cell into a stem cell.

Donating eggs is not a trivial exercise: it is not as simple as donating blood, for example. There is some risk associated with the recruitment and surgical collection of eggs. However, despite these significant consider-ations, many women already altruistically donate eggs to friends and relatives – and even complete strangers – in order to help other women achieve a pregnancy. It could be argued that women would view donating their eggs to research, particularly where their eggs would not be fertilised by sperm, in a very different light to the use of their eggs to conceive a child. Women may opt to donate an egg for research because they have a child or a family member with a disease that is a likely target for investiga-tion. Others may be influenced by what they read or see in the media, or by trusted colleagues and friends.

What we need to ensure is that the information sup-plied to these women, and indeed the patients whose cells would be used in the SCNT experiments, is balanced and in context: that the risks associated with the proce-dure are clearly articulated; that although the promise of the research is great, the technique is still at the stage of basic research and there is no guarantee that their do-nation will result in the generation of stem cells to treat patients or understand a disease. In short, informed con-sent needs to be obtained from the participants.

The obvious way to prevent exploitation is to extend the existing federally administered regulatory frame-

work that governs the use of human embryos in research. Since 2003, the Embryo Research Licensing Committee has granted licences to researchers for the use of human embryos to improve infertility treatments and derive embryonic stem cells only once they were satisfied that the embryos are in excess of the patient’s requirements for infertility treatment, that informed consent would be obtained appropriately and that there was sufficient scientific merit in the proposed research to justify the use of the embryos.

Licence holders also need to be able to account for all embryos used in their research. In Australia, with the passing of the Prohibition of Human Cloning for Repro-duction and the Regulation of Human Embryo Research Amendment Act 2006, we have the opportunity to per-form SCNT. What we now need to see is the modifi-cation of the Licensing Committee ambit to cover the additional issues associated with the donation of human eggs, particularly around informed consent.

While the legislated regulatory framework provides the first tier of protection to prevent the exploitation of community hope, scientists must heed Justice Lockhart’s concerns and continue to discuss their research publicly in a clear and responsible manner. It is only through frank dialogue with patient-support groups and medical practitioners regarding recent scientific progress and its likely benefits that we can attempt to manage communi-ty expectations. Ultimately, medical research is only pos-sible through the support and generosity of the public. No one will benefit if exploitation is allowed to occur.

mEGAn munSIE is the Director of Scientific Affairs and Policy at the Australian Stem Cell Centre. Previously, megan was the Australian Scientific Development manager of the uK listed biotechnology company, Stem Cell Sciences, where she was responsible for the coordination and integration of the Australian group’s research activities within the SCS network and with local and international collaborators. megan is fascinated by all aspects of stem cell biology with a particular interest in derivation and differentiation of embryonic stem cells. In �000, she published the first proof-of-principle for ‘therapeutic cloning’.

sermonIsIng sTem-Cell sCIenCe

By elizabeth Finkelella@finkel.net

Since the discovery of human embryonic stem cells in 1998, stem-cell science has been subject-ed to trial in the court of public opinion. In that court scientists have been called upon as expert

witnesses. It is a position of influence and power. For the lay public the arcane knowledge of scientists makes them as daunting and unchallengeable as high priests.

Over the past 12 months, Australia rumbled through its second-round debate on embryonic stem cells and therapeutic cloning. This ultimately led to the lifting of the ban on therapeutic cloning, and a slight relaxation in the law prohibiting the creation of em-bryos for research. During the course of the debate, we saw many scientists taking the public podium, express-

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ing their expert opinions in newspapers, radio, TV and public lectures. Perhaps now, as the dust settles, it is an opportune time to ask how well scientists performed that public duty. Did they live up to public trust or did they abuse it? Did they fudge the boundary between expert analysis and personal opinion? Did they fail to disclose potential conflicts of interest, religious or com-mercial?

Scientists in the public spotlight walk a difficult tightrope. Real science provides few definitive answers. Yet in the public arena, the fuzzy grey language of sci-ence needs to be sharpened into the black and white of media speak. The risk of that sharpening is overstate-ment. Certainly, scientists have been criticised for ‘hyp-ing’ the potential of stem-cell science. And where those scientists have had associations with stem-cell compa-nies, the accusations of ‘conflict of interest’ have flown thick and fast. But over the past year we saw scientists overstep the mark in a different way.

It seems to me that all scientists should adhere to some basic tenets when they address the public. The first is the limitations of science itself. Though scien-tists may be seen as high priests, science is not in fact about prophesy, and scientists are not able to divine the future. By definition, the long-term results of research are unknowable. Science is replete with surprise and serendipity, where breakthroughs end up coming from left-field, like Barry Marshall and Robyn Warren’s dis-covery of stomach bacteria which led to a spectacularly successful cure for ulcers. In the case of medical research in particular, what we do know is that the success rate is abysmal. Ninety per cent of drugs that enter early-stage trials never make it to the clinic. The key to success in science is to cast the net as widely as possible.

So a scientist has no place prophesying that research using embryonic stem cells and therapeutic cloning will never succeed in producing novel cures, while blithely stating that adult stem-cell research will. This is the gist of the expert opinion we saw from James Sherley, an associate professor from MIT, who was invited to tour Australia by the organisation Doctors Against Cloning. He gave voice to his opinion in public lec-tures (including one at Parliament House, Canberra) and newspapers, as well as appearing on radio and TV.

Sherley also offered extensive ‘expert’ evidence at the October parliamentary senate enquiry. (Back at MIT, Sherley is now on a hunger strike in protest at failing to receive tenure, which he claims is because he is a black American.)

In Australia, Sherley abused his status as a ‘respect-ed’ scientist by fudging the boundary between expert scientific appraisal and personal belief. Sherley did not assist the public to weigh his views against those of other scientists by declaring his potential religious con-flicts of interest. Sherley’s public talks were replete with religious rhetoric but his religious affiliation was not made clear. For instance, his categorical statement that an embryo has an equivalent status to a human being is his personal view, not a scientific or legal fact. This is not to say that a person with a religious affiliation is not capable of being objective about scientific evidence. But the same is true for a person with financial interests in a stem-cell company. If scientists are being trusted to give expert opinion on science, then the public needs to know what potential conflicts of interest may be co-louring their rendition of the evidence.

But scientists also prophesied in other ways that I personally found discomfiting. The Lockhart Review and Senator Kay Patterson’s Bill initially recommended allowing the use of animal eggs as a vessel to attempt somatic cell nuclear transfer (SCNT) – the technical name for therapeutic cloning. While therapeutic clon-ing will ultimately require the use of human eggs, the technique is yet to be mastered.

Given the preciousness of human eggs, in this ex-perimental phase it makes sense to allow researchers to practise with animal eggs. Chinese researchers, for instance, reported success with rabbit eggs. However, in the public arena, politicians scored points against Patterson’s Bill by conjuring alarmist sci-fi scenarios of human–animal chimeras, such as ‘rabbit man’. (In fact, these chimera embryos could only have a transient ex-istence on the laboratory benchtop as they are not vi-able.) Some scientists added ammunition to the oppo-nents’ camp by expressing their scepticism that animal eggs would work in human SCNT, or that their use was unnecessary. At the 11th hour, the clause about using animal eggs was dropped from the Bill. And the Bill fi-

‘ though scientists may be seen as high priests, science is not in fact about prophesy, and scientists are not able to divine the future’

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more guIdelInes, less regulaTIon

By Joe sambrookjoe.sambrook@stemcellcentre.edu.au

In the latest volume of his memoirs, Clive James points out that history consists entirely of con-temporary references that have gone out of date. You could say the same about research in the

biological sciences, which at its best takes chunks of the unknown (or nearly unknown) and by a mixture of intuition, logic and experiment, converts them into neat modules that fit together like pieces of a jigsaw. Although the final picture may be neat and complete,

the process itself is both messy and inefficient, with a lot of redundancy and repetition. But once the dust has settled, the papers have been published and the initial flush of citations recedes, the topic becomes ar-chival and biologists turn their attention to a different chunk of the unknown.

Occasionally though, the traditional pattern shat-ters under the pressure of external forces. This has hap-pened twice in my scientific lifetime. The first was in the 1970s when recombinant DNA first became tech-nically feasible. The second is occurring now, as the re-markable properties of stem cells shimmer temptingly, but are still out of our reach.

In the early 1970s, the basic enzymatic reactions required to construct chimeric DNA molecules were

nally passed in the senate: by one vote! Some will view the jettisoning of animal eggs by scientists as a tactical victory: better to lose a battle and win the war, they say. Personally, I see it as a failure of reason and science.

Scientists may have overstepped the boundary of their duties as scientists, but politicians have been worse. Politicians are not required to shed religious or moral convictions on entering politics. But to what ex-tent is it acceptable to pursue personal religious agen-das while serving as parliamentarians? It is a grey area, no doubt. Surely the boundary would be when those personal agendas start interfering with the letter and spirit of the democratic process.

That boundary seemed very close to being trans-gressed last June, when Howard’s cabinet, strongly weighted by religious conservatives, voted to scuttle the recommendations of the Lockhart Review to lift the ban on therapeutic cloning without a full discus-sion by the party at large.

That boundary seemed very close again during the Senate Committee Inquiry conducted in October, after Senator Patterson’s Bill to implement the recommen-dations of the Lockhart Review had been tabled for senate debate. One would expect the senators conduct-ing these enquiries to behave in an impartial manner in examining the ethical and scientific material that had been submitted to the committee. Instead, the undis-guised prejudice and downright hostility of some of the senators made a mockery of the inquiry process. Some of the senators badgered disabled proponents of thera-peutic cloning with a demeanour that was akin to that of a TV drama courtroom prosecutor. For instance, spinally injured research advocate Joanna Knott was badgered with questions about the status of an embryo

at different ages and what was to stop a ‘slippery slope’ leading to demands for increasingly older embryos for research. As Knott wrote to me: “I’m not an embryolo-gist; I felt like I was on trial.” Dr Paul Brock, an educa-tor and one-time Marist brother who is crippled by mo-tor neurone disease, was appalled by the tone of some of the questions. As Brock wrote to me: “In my profes-sional career I have been involved in quite a few parlia-mentary inquiries, on both sides of the ‘table’. I am used to chairs adopting a relatively disinterested approach to witnesses. For example, when I appeared before the Lockhart Committee, nothing said by Justice Lockhart or any of his other five colleagues on that Commit-tee gave me any idea whatever as to what position or positions they were taking about therapeutic cloning! By stunning contrast, never have I ever seen – no less been subjected to – such partisan belligerence within the context of a government/parliamentary inquiry as demonstrated by Senator Humphries and Senator Fier-ravante-Wells.”

Perhaps in the quiet before the next storm, some reflection on the part of politicians and scientists on the appropriate way to disburse their public duties is in order.

Dr ELIzABETH FInKEL is a correspondent for the uS magazine Science and a contributing editor of Cosmos magazine. She is also a frequent contributor to ABC radio’s Ockham’s razor, the Science Show and the Health report. She has won numerous awards for journalism, including the michael Daley award, mBF awards and Amgen awards. In April �00�, her book Stem cells: controversy at the frontiers of science was published by ABC Books. It won the Queensland Premier’s Literary Award, and was shortlisted for the Victorian Premier’s literary award. She has a PhD in Biochemistry from the university of melbourne and completed five years of postdoctoral research at the university of California in San Francisco. After returning to Australia, Elizabeth traded the laboratory bench for the laptop. She writes for both the scientific and lay audiences.

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worked out at Stanford University and UCSF, and methods were developed to amplify these chimeric molecules in bacteria. Scientists began to dream of us-ing the technology to produce new therapeutic drugs, to generate hardier and more productive strains of agri-cultural plants and to develop new diagnostic tools, but these ideas were still at the drawing-board stage when a great ‘hoo-hah’ erupted within the scientific com-munity that quickly spread into the popular press and eventually into the halls of the US Congress.

In those years, the east coast of the US was home to an irrational and highly vocal cell of left-wing biolo-gists. These people were worried that the nascent re-combinant DNA technology had taken science to the brink of disaster. They felt that the technology would change the course of evolution, could irreversibly alter the environment and might wreak pestilence upon the world by causing novel diseases for which there would be no cures. Their concerns escalated so quickly and so publicly that a voluntary moratorium was placed on all recombinant DNA work in the US until a sober assess-ment of the potential hazards could be made.

In 1975, a group of 150 biologists of all political persuasions met at Asilomar in California to analyse the perceived risks of recombinant DNA and to figure out what to do next. How could the ethical swamps be avoided and the potential hazards controlled, while al-lowing research to proceed in a responsible manner? The meeting began contentiously with people defend-ing fixed positions, but by the third morning a consen-sus was reached that allowed recombinant DNA tech-nology to continue under conditions of strict physical and biological containment. Workable guidelines ap-propriate to the perceived risks were drawn up, pub-lished in the Federal Register and then enforced by the National Institutes of Health.

Over the course of a few years, the guidelines were progressively relaxed as it became clear that the risks of the technology were imaginary and the dangers illuso-ry. Pending legislation that would have severely slowed development was gracefully withdrawn.

In the 30 years since Asilomar, recombinant DNA

technology has revolutionised much of biology – from palaeontology to bioinformatics, from forensics to ge-netics. Genetically engineered drugs – such as insulin, erythropoietin, plasminogen activator, GM-CSF and many, many others produced by a flourishing biotech-nology industry – have saved or extended the span of millions of lives. None of this would have happened, at least not so swiftly or spectacularly, if work on recom-binant DNA had been governed by legislation rather than regulated by guidelines. Asilomar was a success because scientists took the matter into their own hands and were transparent about their dealings.

Unfortunately, Asilomar was the last time that sci-entists could take that degree of responsibility to shape their future. In many countries, decisions about what research is done – including decisions about stem-cell work – are nowadays encased in legislation rather than set by guideline. Even if the legislation is benign, it nevertheless has several problems. By its nature, it is usually highly inflexible and therefore cannot easily be modified to meet changing needs as science evolves. It also stifles the financial investment that is necessary for commercialisation. Venture capitalists are wary of risk-ing money on areas of science that in the eyes of govern-ment need tight regulation.

In Australia, the recent legislative debate about stem-cell research and cloning technology became a highly emotional affair: a mixture of personal views on morality, unhealthy anti-intellectualism and enlight-ened pragmatism. In some respects the debate reflected the decline in public confidence that science can deliver on its promises. It was also the debate that we never needed to have. Science may no longer be an entirely self-governing enterprise, but neither should its prog-ress be restricted by moral confusion.

The next time the stem-cell Act is reviewed in Aus-tralia, we need to follow the example set by Asilomar. We need an overlying law saying that stem-cell research and researchers should strictly follow a set of guidelines that can be reviewed and extended or diluted as the need arises. Scientists can then get back to what they do best – solving chunks of the unknown and fulfilling realistic promises – instead of political lobbying.

JOSEPH F. SAmBrOOK FrS FAA, is Scientific Director of the Australian national Stem Cell Centre, a Distinguished Fellow, Peter macCallum Cancer Centre, and a Professor in the Department of Pathology at the university of melbourne. He is senior author of Molecular cloning: a laboratory manual (known as ‘the Bible’), which over �� years and three editions has enabled generations of scientists to cut, splice, ligate, synthesise, clone, amplify, modify, express and in many other ways manipulate DnA and understand the structure and function of genes.

‘ genetically engineered drugs . . . have saved or extended the span of millions of lives’

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sCIenTIFIC dIsCord sPells Progress

By Vicki saravicki.sara@uts.edu.au

In the recent parliamentary debates on amend-ments to the legislation to allow for somatic cell nuclear transfer (SCNT), also known as therapeu-tic cloning, we saw a number of eminent scientific

opinion leaders put forward opposing arguments relat-ing to the potential value of the science and the ‘state of play’ in embryonic stem-cell research.

The discord revealed on the opinion pages of the nation’s various newspapers, much of it authored by senior scientists from Australia and abroad, often con-fused the public and painted science in a combative light. This discord is a vital and necessary part of scien-tific discourse, ensuring the science is both tested and confirmed. This, in turn, leads to real results for people suffering from real injury or disease.

Another misconception was the expectation that a discovery will inevitably result in a product. Scientific discovery and development rarely evolves in a predic-tive fashion. Development often relies on unexpected inputs, what the public may term ‘failures’, and some-times a fair dose of serendipity. To place a timeframe on when a discovery may reach the bedside is offering the public an unrealistic expectation and encouraging mis-understanding of the nature of scientific discovery and development. This is certainly the case with the hype and hope surrounding stem-cell research.

Thomas Kuhn (1922-96), an American intellectual most famous for a book entitled The Structure of Sci-entific Revolutions, presented the theory that science does not progress via a linear accumulation of new knowledge, but instead undergoes periodic revolutions – that he calls ‘paradigm shifts’– in which the nature of scientific inquiry within a particular field is abruptly transformed. Kuhn’s theory has been hugely influential and equally strongly criticised over the years. You do not need to agree with all of his theory to see that some of what he said can be applied to the nature of progress in stem-cell research.

Stem-cell research, particularly embryonic stem-cell research and SCNT, is in its very early stages of dis-covery and development. Embryonic stem-cell research began to expand following the discovery of the first cell line in 1998; adult stem-cell research had been inves-tigated for 40 years before that. But just like any field of research, biomedical or otherwise, science has always

stem-cell technology

been about pushing the boundaries, encouraging exam-ination and reinvention. Hypotheses are tested, discov-eries are made and, quite often, a new discovery modi-fies or overturns accepted wisdom. There is absolutely nothing wrong with this. In fact, all good scientists wel-come such a challenging approach and process as it makes for intellectual competition: it ensures scientific frontiers are continually tested and it means inaccurate or outdated knowledge will be jettisoned as the new information is discovered. In other words, it is OK for scientists to disagree: this is how progress is made.

Progress in scientific research is often incremental and may take years and the participation of many re-searchers, sometimes in collaboration or competition, sometimes in isolation. Important progress is often made in areas neither apparent nor understandable to the general public, but sometimes with enormous impact on the direction of research in the given field. What we can say in the study of stem-cell research is that the volume of research and rate of publication is in-tense – for example, one journal website (Nature.com) has published 435 articles on SCNT since the govern-ment-appointed legislative review, known as the Lock-hart Review, was completed in late December 2005.

It is vital that both adult and embryonic stem-cell research is pursued collaboratively and in parallel, and the introduction of SCNT pursued. Each of these fields of research holds promise, with many key technologies and discoveries that may serve to enhance both adult and embryonic stem-cell investigations. To shut off or limit one avenue of scientific exploration is to severely curtail that process and limit the potential for signifi-cant improvements in the lives of millions of people suffering from diseases or injuries.

So we should in no way stifle the discord between scientists. We should also not be alarmed at the apparent disagreement and conflicting ‘evidence’ offered within arguments. We should, as the public, view the discourse as valuable and necessary, to challenge the scientific envi-ronment of the day and to ensure the best science comes through. We should also take care not to colour our view with prejudices or fundamental beliefs that, based on specific philosophies, close our mind to the scientific arguments and the refinement of knowledge.

The successful passage of the Patterson Bill allowing the introduction of SCNT is certainly not the end of the debate on the value of stem-cell research. The legislation will be reviewed again in 2010, as foreshadowed in the Patterson Bill, but in the meantime we all have an obli-gation to raise issues as they arise, discuss new develop-ments in the science and try our best to offer context for

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THe gloBal sTem-Cell VIllage

By stephen liveseystephen.livesey@stemcellcentre.edu.au

Science should be seen to be at the forefront of globalisation as it has an extensive international community, with participation in scientific re-search and development practised in all societ-

ies and researchers receptive to ideas from any place on earth. For example, from the end of the 1990s to early 2000, an average of 15 per cent of all inventions in any OECD country were owned or co-owned by a foreign resident, and an average of seven per cent of patents were the result of international cooperation.

The globalisation of science promises to expedite re-search through the division of labour, minimisation of duplication, and specialisation according to comparative advantage, but it also risks undermining the indepen-dence of autonomous groups in a competitive environ-ment. Similarly, regulatory and ethical frameworks that govern areas of scientific research, such as stem-cell sci-ence, are national or even state-based, whereas modern research spans international collaborations with a variety of international funding sources.

Stem-cell science is an exemplary case study in the globalisation of scientific research. Following in the foot-steps of the human genome project, stem-cell scientists across the world are overcoming boundaries imposed by distance, and disparity of interests, funding and legisla-tion, to work in a more coordinated way, while maintain-ing the healthy competition necessary for acceleration of research towards a real clinical result.

Globalisation of stem-cell science is increasingly be-ing shaped by the emerging competitive economies of the Asia–Pacific region. The US and the UK are consid-ered stem-cell leaders by virtue of the size of their scien-tific communities and the speed with which this area of

stem-cell technology

the public as to the value of stem-cell research and the challenges ahead. Scientists will continue to challenge the published evidence and investigate the potential of new technologies, posing a fair and predictable dose of conjecture among the scientific community.

We must remind the public and our politicians that this is a very healthy and valuable environment for our young scientists to learn and our established scientists to progress, and for the public, an important opportu-nity to listen and participate. An open mind to argu-

research has been taken up and investigated. It is prob-ably less well known that Australia has long been a signif-icant player in the stem-cell field. Embryonic stem-cell research was well under way in Australia when Professor James Thompson first published the isolation of a hu-man embryonic stem-cell line in 1998. And in the adult stem-cell field, Australian scientists have been achieving international success for years, led by organisations such as the Walter and Eliza Hall Institute.

The growth of stem-cell networks – a conglomera-tion of scientists in specific geographical regions, with like research or therapeutic interests – is considered by all participants to be a highly successful construct. The formation of national networks was led by the Canadian Stem Cell Network, which was established in 2001 with Canadian Government funding to promote and coor-dinate stem-cell research across Canada. Australia fol-lowed closely with the establishment of the Australian Stem Cell Centre in 2002, funded under the Common-wealth’s Backing Australia’s Ability program. The centre was initially awarded $43.55 million over four years and then an additional $55 million, taking the funding peri-od through until 2011. The centre later received funding support for infrastructure from the Victorian Govern-ment to build and maintain its central laboratories on the Monash University campus in Clayton, Melbourne.

Within a period of three years, stem-cell networks in the mould of the Australian and the Canadian networks have emerged in a number of countries. The UK has six stem-cell networks representing geographical clusters in England and Scotland. Israel, Spain, Japan, and Sin-gapore each have strong, competitive and well-funded stem-cell networks. The US is a significant exception, perhaps due to varying legislation and funding for stem-cell research between states and federal restrictions for the funding of embryonic stem-cell research imposed by the Bush Administration in 2001.

In November 2004, the Canadian Stem Cell Net-work hosted a meeting of international stem-cell net-

ment and respectful ongoing debate always augurs well for improved understanding and real progress.

PrOFESSOr VICKI SArA FAA FTSE, is Chancellor of the university of Technology, Sydney. She was appointed chief executive officer of the Australian research Council (ArC) in July �00�. From September ���� to June �00� she was the chair of the ArC, and a member of the Prime minister’s Science, Engineering and Innovation Council (PmSEIC) and the CSIrO Board. She is chair of the Bureau of meteorology Advisory Board, and a director of the rio Tinto Foundation for a Sustainable minerals Industry and the Australian Centre for Plant Functional Genomics.

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works in Montreal. The outcome of the meeting was a proposal to create an international coordinating group that will be committed to international cooperation and collaboration, extending the concept of national research networks to the international level.

The International Consortium of Stem Cell Net-works (ICSCN), as the group is now known, meets an-nually and aims to unify international efforts to acceler-ate opportunities to make stem-cell therapy a reality for a broad range of debilitating diseases, by: ¢ �providing a forum for scientific and other discussion;¢ �providing a forum for exchange of best practice

and development of international equivalents of national initiatives;

¢ �organising and promoting international workshops and symposia;

¢ �encouraging and facilitating the exchange of researchers between network members; and

¢ �facilitating communications to help in the coordination of research and translation between different countries.The establishment and recent rapid development of

the ICSCN, boasting a growing membership of 14 inter-national stem-cell networks, demonstrates the progres-sive attitude of scientists, funding bodies, governments and industry towards international cooperation.

The ICSCN is co-chaired by Professor Stephen Li-vesey, CEO of the Australian Stem Cell Centre, and Pro-fessor Michael Rudnicki, scientific director of the Stem

Cell Network, Canada. In 2005, the Victorian Govern-ment recognised the importance of international coor-dination and leadership and funded the Australian Stem Cell Centre to host the secretariat of the ICSCN at its Melbourne headquarters.

Within the ICSCN, the US is only represented at a state level, notably by the California Institute for Re-generative Medicine, which is not a network of a similar structure to the rest of the world. However, it could be considered the closest agency the US has developed that enables them to join the global community of networks. Following a landmark election ballot that passed crucial legislation (Proposition 71) allowing embryonic stem-cell research and therapeutic cloning technology to take place in California, the California Institute for Regen-erative Medicine was established, with $3 billion, to be raised over 10 years via a bond issue, to be distributed to scientists in California.

One of the newest and most interesting stem-cell communities is the Stem Cell Research Forum of India (SCRFI), which recently held its first annual stem-cell conference in Bangalore with great success. The SCRFI is an initiative of the Indian Department of Biotechnol-ogy to create a coordinated national stem cell initiative. The SCFRI’s role is similar to that of the Australian Stem Cell Centre in that it must prioritise research funding, focus on clinical applications and promote stem-cell ‘clusters’ to ultimately deliver therapeutic results. The initiative is intended to continue for at least a decade.

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Australian Stem Cell Centre

Bereshith – Israeli Consortium for cell and stem cell therapy

California Institute for Regenerative Medecine

International Society for Stem Cell Research

RIKEN Centre for Developmental Biology, Japan

Scottish Stem Cell Network

Spanish Stem Cell Network

Stem Cell Network North Rhine Westphalia

Stem Cell Network, Canada

North East England Stem Cell Institute

Network in Regenerative Medecine, Berlin

Norwegian Centre for Stem Cell Research

Stem Cell Research Forum of India

New York Stem Cell Foundation

SOURCE: www.stemcellconsortuium.org

ICSCN MEMBERS 2007

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aupresident’s message

By robin Batterhamrobin.batterham@riotinto.com

It is an honour and a privilege to follow in the footsteps

of the luminaries who precede me as Presidents of the

Academy of technological sciences and engineering. it

is also a challenge. the challenge is the changed nature of

science and technology and the role that a learned academy

might play. the fellowship of the Academy comprises

a body of eminent Australians who have distinguished

themselves in science, engineering and technology (set).

the Academy is renowned for authoritative advice on

matters of importance to Australia and wider afield, for its

activities through the crawford fund and the clunies ross

foundation, and of course for its long-standing role of

offering advice to government.

however, the changing nature of science, engineering

and technology forces us to focus. there are broad

challenges that need to be addressed.

first, the amount of knowledge available is expanding

at an exponential rate. some estimates put the doubling

time at less than four years. even if we discount this rate

– as some knowledge is duplicative or of lesser value – the

exponential rate remains. this is a formidable challenge

for anyone engaged in set to remain current in an ever-

expanding field. how can you offer advice if the field is

shifting so rapidly?

Part of this expansion is the process of convergence,

where developments in one area have a dramatic influence

on another. New disciplines such as bioinformatics

emerge, or applications are forever appearing, such as

the use of principles of insect vision in guiding robots

and autonomous vehicles. this process of convergence

applies across all disciplines. it has been estimated that

the combination of genomics, implants and cognition

enhancements may converge to extend life, such that the

first person to reach a healthy 150th birthday may have

already have been born.

the fellowship of the Academy represents a vital

network of high-level capabilities spanning all the

disciplines of set. one challenge will be how to bring

cross-disciplinary comment to bear on issues, including

the wider fields of the social sciences and humanities. this

issue of Focus, with its emphasis on stem-cell technology, is

a good example. does Focus reach out far enough? should

it encourage more debate on topics per se? some debates

can be uncomfortable, but nevertheless worth having.

As an Academy, we do not have to come to an agreed

position and in most cases probably will not. how do we

get more involvement and debate? i am not yet convinced

of the value of blogs, but online contributions might be

a way to go. on the one hand we have a scanlon report

emphasising the need for more investment in water, a

recent intergovernmental Panel on climate change (iPcc)

comment on oceans and global warming, and our fellow

lance endersbee suggesting that the use of groundwater

resources over the past century has added a large amount

of new water to the hydrosphere commensurate with the

observed raising of the sea level. Where is the debate?

A further challenge is recognition that innovation drives

the growth of the economy and generates our choices in

life. however, innovation is a lot more than just r&d. it is

as much about effective execution. the Academy has a lot

to offer here. our fellows have the experience of effective

VOLUME OF INFORMATION PRODUCED A YEARVolume (Exabytes*)

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SOURCE: Dr Oliver Sparrow, The Challenge Forum www.chforum.org

challenges for a new President

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execution and a deep understanding of what works and

what does not. but we must be realistic in that we face ever-

increasing expectations – including those of energy security,

product stewardship, sustainability and the quality of life

– against a background of disenfranchisement with science

and technology, a lack of knowledge of the role of engineers

and technologists (and scientists, for that matter) and

questions as to the best path for science and technology

education from kindergarten through to university.

overall, i think we need to focus upon a few major

activities and a range of smaller-scale, but worthy,

undertakings. i have in mind working up a simplified

strategy so that it can guide all of us in how we contribute

to the Academy. i find the strategic Plan of the royal

Academy of engineering worth inspection. if i were to

paraphrase it and shorten it even further for our conditions,

it would be that Atse exists:

¢ �to celebrate excellence and inspire the next generation;

and

¢ ��to lead debate by guiding informed thinking and

influencing public policy.

i see us using such a strategy and concentrating our

efforts for the next few years on a limited number of key

areas such as water, energy and climate change, together

with making a difference in education. is there room for one

or two other key areas?

And so over to you the fellowship: am i reading the

purpose of the Academy correctly? is a more limited set

of key areas likely to enhance our objectives and the

essential participation of fellows? should we encourage and

stimulate much wider debates in our efforts to influence

public policy?

the recent publication of the scanlon report suggests

that quite drastic changes are going to be needed over the

next 30 years.

so challenges abound! i look forward to my two-year

term as President of the Academy and hope that we can

provide some timely advice, based on the marvellous

base of experience that exists in the fellowship, to help all

Australians better rise to the challenges of a runaway world

in which the knowledge base, and hence the opportunities

and competition, are increasing exponentially.

PrOFESSOr rOBIn BATTErHAm AO FAA FTSE is Global Practice Leader – Innovation, Operational and Technical Excellence, rio Tinto Ltd, and a Professorial Fellow in the Department of Chemical and Biochemical Engineering at the university of melbourne. He has had a distinguished career in research and technology, in the public and private sectors. He was Chief Scientist for the Australian Government from ���� to �00�. He worked with CSIrO in areas such as mining, mineral processing, mineral agglomeration processes and iron making. He is Past President of the Institution of Chemical Engineers, Chairman of the International network for Acid Prevention and President of the national Science Summer School.

At present, China is a notable absentee from the membership of the ICSCN. Like India, China is invest-ing heavily in stem-cell research across the country and has an active program to bring exceptional expatriates home to run their own laboratories. However, as yet China has no national or even state-based networks, and the approach to funding is only loosely coordinated between government departments and regional funding bodies. The main hubs for stem-cell research in China are Beijing, Shanghai and Changsha. The ICSCN has had many approaches from Chinese researchers to join the consortium, and is working with China to establish a national network.

The initiative and funding for networks is nearly al-ways that of governments’ industry or innovation depart-ments, rather than science or health. One might deduce that this is because governments have clearly recognised the value of biotechnology to the economy. In December 2005, the total value of publicly traded US biotech com-panies was US$410 billion. The Biotechnology Industry Organisation estimates that the US biotech industry has mushroomed since 2002, with US healthcare biotech revenues increasing from US$8 billion to US$50.7 bil-lion in late 2005. This has occurred even though the biotech industry is one of the most research-intensive in-dustries in the world, with enormous risk and significant rewards. Governments recognise that biotechnology and information technology are two of the most likely winners in emerging knowledge-based economies.

The value of a collaborative approach to the success-ful and expeditious advancement of stem-cell science cannot be calculated. This is unknown territory. The global consortium approach, being led by the Australian Stem Cell Centre, is built on the premise that a coordi-nated international effort will increase the probability of a therapeutic outcome being brought to market sooner. Collaboration will stimulate competition and the com-petitiveness of stem-cell research in general.

Whether the first therapeutic outcome is a new drug, treatment, diagnostic tool or cell therapy, my mon-ey is on it being a discovery that reaches across national boundaries.

PrOFESSOr STEPHEn LIVESEy is CEO of the Australian Stem Cell Centre, returning to Australia in �00� to take up the post. He was co-founder and formerly Executive Vice-President and Chief Science Officer of LifeCell Corporation, new Jersey. A graduate of the university of melbourne, he was Associate Director of the Cryobiology research Center at the university of Texas, and a Wellcome Trust Senior research Fellow at St Vincent’s Institute of medical research, melbourne, in ��88. In ����, he became Vice-President of Scientific Development of LifeCell Corporation, and in ���� Executive Vice-President and Chief Science Officer. Professor Livesey is the inventor of the company’s tissue matrix and cell-preservation technology.

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wHo deTermInes medICal researCH’s Value?

By alan Trounsonalan.trounson@med.monash.edu.au

There is now a stage play about how governments approach legislation on stem-cell research. In her review of the play, Eva Amsen of the Uni-versity of Toronto writes: “It’s intermission

and everybody milling around me is talking about stem cells. We’ve just seen the first half of Chimera, a world-premier play that explores the murky world of stem-cell ethics and legislation – how lawmakers with no background in science should decide what to ban and what to permit.” Certainly much of her review will resonate strongly with impartial observers (if there are any) on the processes we have adopted to determine the boundaries and penalties of research involving embry-onic stem cells.

The debates surrounding in vitro fertilisation (IVF) in the late 1970s and 1980s led to a patchwork of state laws, which had the effect of moving the IVF research and innovation from Australia to other places such as the UK, Belgium, the US and Sweden. Despite the very heated ethical debates, religious opposition and claims at the time of IVF as a “flawed and failed technology”, there are now more than four million IVF births world-wide. Indeed, most people know families that have had an IVF child, and around two to three per cent of all births in Australia and New Zealand are a direct con-sequence of IVF. Most types of male and female infer-tility can be treated by the new assisted reproductive technologies (ART), and genetically inherited disease can be diagnosed in the early embryo, so couples at risk of having severely affected children can now use ART to avoid the distress of therapeutic abortion.

My participation in ART led me and my colleagues to explore the possibility of generating embryonic stem cells, which, together with the landmark work of James Thompson in Wisconsin, has led to a revolution in medical research into cell therapies involving stem

cells. There are claims and counter claims from scien-tists about the potential of different types of stem cells, their applications and early clinical results, which you can expect in any rapidly moving and highly complex scientific research field. This is a normal part of the pro-cess that determines what is safe, effective and reliable in medical therapies. Stem-cell research is advancing on numerous fronts all over the world, and the studies in different types of stem cells cannot be extinguished.

Clinical trials are under way with many adult stem-cell types. Some are effective, as in renewal of blood cells by bone marrow transplantation, others are of du-bious clinical benefit and sometimes the results are not repeatable. It is generally held that new basic research results require independent confirmation in several lab-oratories before they are accepted as real and reliable. Hence, the longer a science spends at basic studies, the more predictable and reliable the eventual clinical out-come. This bodes well for applications of embryonic stem cells (ESCs). The first formal clinical trials involv-ing ESCs are proposed to begin in 2007 in the US for attempted spinal repair. What is apparent is that robust cell models for drug-discovery purposes are probably very close. These may include the production of differ-ent types of neurons, heart muscle and blood cells. New drugs for treating human diseases are likely to evolve from this work.

Who decides, or who should decide, what new medi-cal research is acceptable or appropriate? Scientists must explain the opportunity; patients who may benefit must voice their support; and the community must be given time to understand the basics of the science and what it may provide as potential new medical therapies.

Christopher Reeve told me that the hope of a cure, no matter how slim, gave him the will and capacity to contribute to the broader community interests that en-riched his life, despite his very severe health problems. For many patients, it is necessary to believe that quality of life may be better tomorrow and that some recovery is possible. Cell therapy remains the hope for a very large number of people with severe health problems. For both patients and scientists, it is incredibly frus-

‘ for both patients and scientists, it is incredibly frustrating to be denied the opportunity to participate in research because of philosophical, political or religious opposition’

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reCenT adVanCes In sTem Cell-researCH

By nick goughthegoughs@ozemail.com.au

In 2006, during the Senate Inquiry into the Lock-hart Review, progress made in the field of embry-onic stem (ES) cell research was questioned by many opposed to stem-cell research in general and

to legislative changes proposed by the Lockhart Review in particular.

Such assertions that progress had been slow typi-cally drew one of three responses:¢ �‘Catch 22’ – since certain stem-cell technologies

(notably somatic cell nuclear transfer involving hu-man cells) were banned, substantial progress could not be possible;

¢ ��medical research takes time – we do it for our children not for ourselves; or

¢ �but there has been progress!Since human ES lines were first derived in 1998,

some 75 fully characterised lines, and perhaps as many as 300 in total, have been derived worldwide. For cells derived from human ES cells to be deployed in a clinical setting, and to represent commercially viable, clinically valuable and routinely applicable therapeutic modali-

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trating to be denied the opportunity to participate in research because of philosophical, political or religious opposition.

I salute the medically interested members of Fed-eral Parliament who carried the day in the recent de-bates over the Kay Patterson Bill, which reflected the recommendations of the Lockhart Review Committee. I think the community wants to learn about science and medicine, and is capable of assimilating the infor-mation provided in a way that enables a decision. The strong community and patient support, and a process that enabled a ‘conscience vote’ for political endorse-ment, must be lauded.

There is a general tendency to want to manage in-formation to achieve particular legal and regulatory outcomes, which is a concern in science where all the options need to be tested and explained. Risk manage-ment should be about the quality of research and re-liability of outcomes, not the information flow to the community. It needs to be understood that stem-cell therapies are generally yet to be tested widely in prop-erly conducted clinical trials.

ties, a number of issues must be addressed and satisfac-tory solutions obtained. Key advances are summarised in this article.

growth of human es cellsTo date, most human ES cells have been propagated us-ing systems that are manually intensive, inefficient and involve complex components in the tissue-culture envi-ronment, typically co-culture with other ‘feeder’ cells. A typical research laboratory may be able to produce 108 to 109 cells a week, many orders of magnitude less than required for clinical trials and commercial pro-duction.

Systems ultimately to be used, clinically and com-mercially, need to be simple, reproducible, scaleable, automatable, cost-effective and, most importantly, compliant with exacting standards of Good Manufac-turing Practice (GMP).

Significant progress is being made, with numer-ous reports now suggesting that human ES cells may be grown in feeder-free, serum-free, scaleable culture systems.

generation of clinically acceptable human es cellsTo date, most human ES cells have been derived and propagated in culture systems that potentially limit

While some optimism that patients will benefit is necessary for clinical trials based on supportive data from preclinical studies usually involving animal models of human diseases, the benefits and the best type of the stem cell to use remain to be determined. There is now optimism in the international research community that because of the very widespread community support of this science, progress will not be unduly hindered and the outcomes will be rewarding in the development of new cell therapies for treating at least some of the pa-tients afflicted with the more than 70 conditions that are the present targets for stem-cell therapies.

PrOFESSOr ALAn TrOunSOn is Professor of Stem Cell Sciences and Director of the monash Immunology and Stem Cell Laboratories at monash university. He is also Founder of the national Biotechnology Centre of Excellence (the Australian Stem Cell Centre) and is its Global Scientific Strategy Adviser. His scientific accomplishments include the pioneering of human in vitro fertilisation (IVF) and associated reproductive technologies, the diagnosis of inherited genetic disease in preimplantation embryos, and the discovery and production of human embryonic stem cells and their ability to be directed into neurones, prostate tissue and respiratory tissue. He is a member of the Victorian Government’s Innovation Economy Advisory Board, and is a Director of the Victorian Endowment for Science, Knowledge and Innovation (VESKI).

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their acceptability for clinical use, including use of non-human ‘feeder’ cells, non-GMP-compliant ani-mal-derived products (such as foetal calf serum and other non-GMP-compliant reagents) and procedures for obtaining embryos, deriving cell lines and establish-ing master cell banks.

The US Food and Drug Administration (FDA) has made it clear that therapies involving stem cells from embryos (or adults) will be regulated as drugs, requir-ing exacting standards of purity and potency be met. The European Union has also made similar directives.

Thus, there is a significant push to derive and prop-agate new human ES cells under clinically compliant GMP conditions. In order to achieve this a number of specific issues must be addressed, including:¢ �GMP-compliant, preferably human feeder cells

and GMP-compliant growth systems for them; or systems that do not require additional feeder cells;

¢ �GMP-compliant human ES growth media and propagation processes;

¢ �GMP-compliant cryopreservation protocols; and¢ ��a GMP-compliant master cell bank.

Moreover, embryos from which ES cells are de-rived would themselves also need to be obtained under GMP-compliant protocols.

Significant progress has recently been made in this regard, with a number of reports of derivation of new human ES lines under conditions that partially, or possibly completely, address these requirements, and which if substantiated would potentially remove one of the biggest hurdles to ultimate clinical utility of human ES cells.

Production of medically relevant tissues from human es cellsAlthough advancing, the ability to produce a range of medically relevant cell types from human ES cells is still at a relatively early stage. There have been a number of reports about human ES cells being coaxed to produce various mature cell types. Importantly, several recent studies have reported promising, therapeutically rel-evant function of cells/tissue derived from human ES cells when transplanted into animal models of various human diseases, including:¢ �dopaminergic neurones capable of promoting

partial behavioural recovery in rat and primate models of Parkinson’s disease;

¢ �cardiomyocytes that can restore heart rate when grafted into a pig model of impaired cardiac function;

¢ �oligodendrocyte progenitor cells capable of

enhancing re-myelination and promoting improvement in motor function when transplanted following spinal-cord injury in rats;

¢ �pancreatic islet cells capable of short-term reversal of hyperglycaemia in diabetic mice; and

¢ �muscle precursor cells that are capable of incorporating into regenerating muscle fibres in mice.

overcoming transplantation barriersDifferentiated cells derived from human ES cells are likely to express human transplantation antigens that will potentially cause rejection of transplanted cells. Thus, strategies to overcome or avoid graft rejection without broadly suppressing immunity may be needed.

Development of cell banks with ES cells of diverse tissue types has been advocated, enabling traditional approaches of tissue-matching combined with conven-tional immunosuppressive therapy (as used for organ transplantation). A recent simulation in the UK esti-mated that a bank of some 150 human ES lines could provide a beneficial match for 25 to 50 per cent of po-tential recipients and a 95 per cent chance of providing a full match for at least eight per cent of patients.

Another strategy for avoiding graft rejection would be genomic replacement by somatic cell nuclear trans-fer (SCNT), in which the nucleus from a somatic cell from an intended recipient would be used to replace the genetic material of an oocyte, thereby generating a matched-donor stem-cell line. Although generation of personalised ES cells by SCNT for a specific patient is a theoretical option, it is unlikely that production of personalised tissues by genomic replacement would represent a practical strategy for each and every patient. However, SCNT may represent a viable approach to ensuring inclusion of rarer tissue types in a human ES cell bank, thus enhancing the impact of that approach.

In the longer term, other strategies will doubtless develop in which immune tolerance to the donor hu-man ES-derived tissue is induced in the recipient pa-tient. Indeed, Fändrich and colleagues were able to induce long-term acceptance of heart transplants in rats by injecting rat ES-like cells (of the same type as the ultimate heart transplant) into non-immunosup-pressed recipient rats. The injected ES cells persisted in the recipient leading, it would seem, to immunological tolerance. The underlying mechanism involved and its broader applicability are yet to be established.

Clinical trials involving human es cellsMost human ES-based clinical trials are a number of

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years away, although Geron in California plans to initi-ate a clinical trial with human ES cell-derived oligoden-drocyte progenitor cells to treat spinal-cord injuries, currently foreshadowed for 2007.

Benchmarking progressSo how well is human ES cell research doing? By analo-gy with dendritic cells, another complex new cell-based therapeutic modality, very well. A number of new treat-ments based on use of dendritic cells targeted against specific cancers are now in advanced clinical trials. Dendritic cells were first identified as potent immune cells in the mid-1980s. In order to develop therapies based on these cells, numerous complex issues associ-ated with obtaining the cells, activating them in vitro, returning them to a patient and so on (all under ex-acting standards required by the FDA to develop and

PersonalIsed sTem Cells: PoTenTIal and Hurdles

By Paul J. Vermapaul.verma@med.monash.edu.au

By voting to amend the human embryonic stem-cell (hESC) legislation laws in Decem-ber last year, the Federal Government has expanded the medical research frontier for

Australian scientists. This decision should pave the way to investigate and understand cures for a range of de-bilitating diseases and conditions. In addition, it will keep Australian scientists at the forefront of stem cell research. The Prohibition of Human Cloning for Repro-duction and the Regulation of Human Embryo Research Amendment Act 2006 allows researchers to generate human embryos specifically for research and to derive hESC lines from them, and to conduct human somatic cell nuclear transfer (SCNT) research.

Many believe such research is critical to understand-ing and eventually alleviating a range of incurable/un-treatable conditions including:¢ ��degenerative diseases (such as Parkinson’s, Alzhe-

imer’s) where specific cell types in the body degen-erate as the disease progresses;

¢ �uto-immune diseases (such as type 1 diabetes) where the body’s immune system attacks its own cells;

¢ �conditions of tissue damage (such as spinal cord in-juries, heart attack);

¢ �genetic disorders (such as sickle-cell anaemia, cystic fibrosis, Down syndrome); and

ultimately market specific therapeutic products) have needed to be solved. It has taken dendritic cells some 20 to 25 years to progress from observation and idea to candidate products in advanced trials, during which time a range of complex and challenging issues have been solved. Against that backdrop, I am confident that similar issues and challenges faced by human ES cells will also be solved, and that current progress is bench-marking very well.

nICK GOuGH FTSE was research Director of AmrAD Corporation, CEO of ExGenix Ltd and Director of the Gene CrC. He has extensive experience locally and internationally in both biomedical research and in the biotechnology industry. He has a PhD from the Walter and Eliza Hall Institute, where he also held a senior research position. He is an inventor of technologies underpinning a number of biopharmaceuticals – the new breed of genomics-derived drugs – one in routine clinical use internationally and others in clinical trials and preclinical development. He now acts as a freelance biotechnology consultant.

¢ �degeneration of complex organs (such as kidneys).ESCs have two salient properties: they can self-

renew or undergo differentiation, depending on the biochemical cues they receive. The cells are termed ‘pluripotent’, meaning they have the potential to dif-ferentiate into any cell type and this, along with their property of self-renewal, provides a limitless source of cells for research or transplantation. A key issue in the ultimate clinical use and commercialisation of stem-cell therapy is the source of stem cells used to generate the cells for transplantation. Human ESC lines express parental human leukocyte antigen (HLA) types, and their derivatives will be immunologically disparate from potential recipients and are therefore likely to elicit immuno-rejection following transplantation, un-less the cells are transferred to immune-privileged sites.

The earliest biomedical benefits are envisaged not from therapeutic use, but in the understanding of dis-eases and the potential to aid in an early diagnosis of debilitating diseases. For example, if we could generate an ESC line from a patient suffering from a disease such as Parkinson’s, where specific cells, namely dopaminer-gic neurons, degenerate after onset of the disease, we might study the progression of disease in the labora-tory dish. This could be achieved by inducing the ESCs with a predisposition to the disease to differentiate into dopaminergic neurons in vitro.

Understanding the disease could make it possible to diagnose children who are susceptible, and work to-wards either prevention or cure. ESCs derived in this way could also be used as screening tools to develop drug therapies for various diseases.

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In Australia, until now, ESC lines have only been produced from normal embryos surplus to IVF, as the legislation for research on genetically abnormal embry-os was not clear and varied between the states and terri-tories. This precluded the generation or use of embryos identified as harbouring disease for ESC isolation. Diseases caused by single-gene mutations such as cystic fibrosis, or single-chromosome defects such as Down syndrome, can be identified by pre-implantation ge-netic diagnosis (PGD) of IVF embryos before embryo transfer to the uterus. Derivation of ESC lines from these embryos should be relatively straightforward.

However, the generation of ESC lines of complex genetic diseases, such as Parkinson’s and Alzheimer’s, influenced by multiple genes possibly located on differ-ent chromosomes that manifest only in adults, would be logistically impossible to achieve from randomly collected IVF embryos, unless we generate ESC lines from adult patients with the disease.

A number of approaches have been proposed to achieve individual-specific or ‘personalised’ ESCs from an individual whose cells have already completed differ-entiation. The only technique shown to work so far in animal studies is somatic cell nuclear transfer (SCNT), which involves the transfer of an adult cell nucleus to an enucleated donor egg. This reconstructed SCNT embryo is cultured to generate a blastocyst and ES cells are isolated from it.

The current limitations to SCNT in humans are ethical, logistical and scientific.

Sourcing unfertilised eggs to conduct the research will pose a significant hurdle in Australia, where we have a system of altruistic donation for all tissues in-cluding organ and blood donation. On the scientific front, SCNT in primates, including humans, has prov-en difficult and inefficient in the few studies conducted overseas. Alternative approaches are being investigated for reprogramming adult cells to an ES-like state. One

such method involves fusion of adult cells with ESCs to effect reprogramming. Other techniques attempt ‘de-novo’ reprogramming by either exposure of adult cells to reprogramming factors or forcing expression of pluripotent (ESC) genes in the adult cells. These approaches have yet to be robustly demonstrated in animal models, but would be extremely valuable and practical if successful.

Based on the efficiency of the current SCNT tech-nology, the feasibility of producing specific cells for individual patients seems unlikely in the foreseeable future. However, a study published in The Lancet sug-gests SCNT could be invaluable to generate ESC lines with specific genetics to maximise the HLA-matching of ESC banks with patients.

In the study, the authors reported that the genera-tion of 150 or 1500 ESC lines from randomly sampled individuals (or embryos) would provide an exact HLA match to both the major histocompatibility complex (MHC) Class I & II molecules for 18.5 per cent and 32.1 per cent, respectively, of about 6500 patients on the UK kidney transplant waiting list, whereas just 10 carefully selected individuals would provide an exact match for 37.7 per cent of the same group of patients. SCNT would be an efficient means to produce ESCs from those 10 selected individuals.

The amendments to the legislation will allow key stem-cell research to be conducted in Australia in an ethical, tightly regulated and controlled manner. This research is not about cloning mankind, but about mak-ing life healthier for a number of patients suffering from incurable, debilitating conditions.further reading: taylor et al 2005 Lancet 366: 2019-2.

Dr PAuL J. VErmA is a Senior research Fellow at the monash Institute of medical research. He heads a research group investigating cell reprogramming, embryonic and adult stem cell isolation and somatic cell nuclear transfer in mammals. He is co-editor of the book Nuclear Transfer Protocols: Cell Reprogramming and Transgenesis.

sPare a THougHT For our negleCTed genes

By John raskoj.rasko@centenary.usyd.edu.au

While my colleagues in this edition will con-centrate on stem-cell technologies and the controversies that have recently raged, this brief commentary seeks to refocus some

attention on clinical gene therapy.

Recent decisions by the Australian Government, following recommendations made by the Lockhart Re-view, have allowed embryonic stem (ES) cell research to proceed, and increased funding has been made available through the Australian Stem Cell Centre. However, it could take at least another decade before the best thera-peutic applications of ES cells and adult stem (AS) cells begin to be resolved. Meanwhile, over the past decade, a quiet revolution has occurred, with unambiguous triumphs for gene therapy of several severe inherited disorders. Success in human trials leading to cures for

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diseases such as severe combined immunodeficiency and chronic granulomatous disease have not been ap-propriately celebrated, owing to some disastrous initial trials that set the field back, complications in a minor-ity of patients and a past history of ‘hype’ that sullied the field.

Demonstrable advances in gene transfer efficien-cies, improvements in the safety profile and technolo-gies designed to monitor genomic mutations have contributed to a situation where clinical gene therapy may now move rapidly from proof-of-principle to the treatment of diverse human diseases.

This relates to stem-cell technologies because the introduction of therapeutic genes may only lead to benefit in a cellular context, where the machinery to express the new genes is available. These target cells may be embryonic or adult stem cells, as well as their cellular progeny. As such, gene therapy has always maintained a special interest in stem-cell technologies, arising first in efforts to genetically modify the haemopoietic stem cell for diseases like thalassaemia and sickle cell disease.

Historically, many members of the gene therapy community have received their basic clinical training in haematology or immunology. Of course, target cells may be gene-modified in vivo or ex vivo, but either way a firm grounding in most aspects of transplantation bi-ology and immunology is required to overcome some of the obstacles challenging gene therapy.

Australian scientists and physicians continue to contribute substantially to progress in cell and gene therapies. In mid-2007, Australia becomes the focus as Australian and international stem-cell scientists con-verge on Sydney and Cairns for the annual meetings of the International Society for Cellular Therapy and the International Society for Stem Cell Research.

Although opponents of ES cell research frequently promoted the promises of AS cell research to confuse the public, the fact is that both areas of research re-quire funding until they are sufficiently mature to al-low head-to-head comparisons in randomised clinical trials. Given the fact that human ES cell lines have only been established since 1998 and have yet to be tested in humans, it is inconceivable that fair comparisons could be made to AS cell technologies which, for hae-mopoietic stem-cell transplants, have been saving lives for decades.

The renaissance in AS cell biology has arisen due to the identification of previously neglected stem-cell populations in specific organs, and a realisation that stem cells enriched from certain organs, such as the bone marrow and cord blood, may have the potential

to contribute to other tissues (exhibiting increased ‘plasticity’). For example, mesenchymal stem cells, a type of AS cell first described by Friedenstein in the 1970s, are being tested from preclinical to phase III clinical trials for diverse serious afflictions, including graft-versus-host disease, Crohn’s disease, degenerative joint and connective tissue diseases and osteogenesis imperfecta. The genetic modification of mesenchymal stem cells is being actively studied as a means of target-ing anti-cancer therapies, for example in prostate can-cer, and to create in vivo cellular factories for hormones and cytokines.

Similar opportunities exist for other stem-cell pop-ulations, including those from the brain, cord blood, neural crest and liver, and for differentiated cell popula-tions including dendritic cells, lymphocytes, myocytes, immunogenic cancer cells and pancreatic islet cells.

A phenomenal proof-of-concept and technical tour de force in combining ES cell and gene therapy was achieved in 2002 by a group led by Rudolf Jae-nisch. In a mouse model, mature fibroblast nuclei from Rag2-deficient animals were used to create autologous embryonic stem cells, which were then genetically re-paired by homologous recombination and differenti-ated from embryoid bodies into haemopoietic stem cells, with the assistance of a gene therapy vector ex-pressing the HoxB4 transcription factor. These autolo-gous, gene-repaired haemopoietic stem cells could then be used to reconstitute the donor to cure the immune deficiency and provide a new paradigm for ‘therapeutic cloning’.

Perhaps the most important clinical example of combined cell and gene therapy is the successful trial involving children with X-linked severe combined im-munodeficiency (SCID-X1), first initiated by Alain Fisher and colleagues in Paris. For the ‘boy in the bub-

‘ over the past decade, a quiet revolution has occurred, with unambiguous triumphs for gene therapy of several severe inherited disorders’

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ble’ who lacked a compatible bone-marrow transplant donor, their own haemopoietic stem cells were gene-modified ex vivo to express the normal version of the common gamma chain responsible for transducing the signal of six interleukins.

The initial results, reported widely in the top jour-nals, were miraculous. These children recovered a nor-mal lymphocyte count and grew a new thymus as their immune-progenitor cells were now able to respond to the proliferative signals normally present in their bod-ies since birth. The cruel infectious diseases that had overwhelmed their bodies prior to the cell and gene therapy resolved and they were able, in most cases, to return to a near-normal childhood.

Of 18 children treated in the Fisher protocol and a subsequent trial initiated by Adrian Thrasher in the UK, three developed a lymphoid leukaemia in their gene-modified cells. Although the exact explanation for the leukaemias remains a matter of scientific de-bate, it is clear that activation of a known oncogene, LMO2, following genomic insertion of the relatively early-generation retroviral vector contributed substan-tially. Leukaemia had always been acknowledged as a possible consequence of retroviral gene therapy, but the high frequency observed in the SCID-X1 trial was not anticipated. Neoplasia has neither been observed in many other retroviral human gene therapy trials nor confirmed in prospective safety trials involving non-hu-man primates.

Additionally, most investigators believe that tech-nical advances in vector design, as well as newer len-tiviral systems, will reduce the occurrence of such ge-notoxicity. Nevertheless, a major consequence of this tragic complication has been enormous efforts interna-tionally to overcome the problem of insertional muta-genesis and most, if not all, clinical trials must provide costly, possibly lifelong, monitoring of recipients’ cells at the clonal level. Examples of ‘ecstasy and agony’ have been a feature of combined cell and gene therapy, but the inescapable conclusion is that humanity now has a tool that can be used to modify inherited diseases. The time has arrived to initiate trials in diseases that extract the highest human tolls: cardiovascular, neuro-degen-erative, diabetes, those affecting bone and joint and, of course, cancer. The capacity to undertake human clinical cell therapy trials in strictly regulated ‘good manufacturing practice’ laboratories has recently been boosted by funding from the National Collaborative Research Infrastructure Strategy.

Combined cell and gene therapy in Australia is now at a crucial point in its history. Investigators in

Europe and the US have led this field and, in general, the relatively few Australian units involved have done so via collaborations established through personal con-nections. The US established a few national gene vector laboratories over a decade ago that have manufactured at least three dozen gene therapy vectors for trials in over 300 subjects. Many European countries have na-tional or not-for-profit gene therapy vector production facilities, but nothing similar exists in Australia.

In recent months, recommendations from the American Society of Gene Therapy and an NIH-ap-pointed committee have highlighted the problems of short-term funding for necessarily long-term clinical gene therapy trials and the intricate web of near-im-penetrable regulatory committees. The problem here is that even if proof-of-principle and preclinical safety are demonstrated using appropriate animal models, Aus-tralia lacks the considerable funding infrastructure to sustain a clinical program in cell and gene therapy.

A substantial risk exists that Australia will lag be-hind in developing the infrastructure and expertise required to take advantage of the substantial progress expected to occur in the coming years, not to mention lost opportunities to create and protect intellectual property created here. This is precisely the rationale for establishing Australian initiatives in explicit funding for stem-cell research.

What is therefore required is a reinvigoration of funding for gene therapies, to build upon the national commitment for stem-cell research.

During my tenure as President of the Australasian Gene Therapy Society, an approach was made to the National Health and Medical Research Council in 2004 to create a gene therapy grant review panel. At the time, this proposal was not acted upon and may not, in retrospect, have provided the best means to promote this field, owing to the long-term funding commit-ments required. Whatever funding vehicle may be used, the time is ripe for a substantial injection of sustained funds exclusively allocated to support novel combina-tions of cell and/or gene therapies. Genes need a safe place to work their magic too!

PrOFESSOr JOHn rASKO FrCPA FrACP directs Cell and molecular Therapies at rPA Hospital and heads the Gene and Stem Cell Therapy Program at the Centenary Institute, university of Sydney. His was the first formal appointment in clinical gene therapy in Australia. Professor rasko has been successful in uncovering new mechanisms of leukaemia, understanding cytokine mechanisms of action and clinical trials of new biological therapies for cancer and bleeding disorders. In �00�, he led a team that identified the gene for Hartnup Disease, and most recently contributed to a milestone in gene therapy for haemophilia.

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Food, waTer and PHosPHaTe

By John swanj.m.swan@bigpond.net.au

The flow of phosphate from farm to city to waste disposal is not good news. My interest in this topic was stimulated by the work of Professor A. Duncan Brown as described in his book Feed

or Feedback. A one-sentence synopsis might be ‘how famine looms as phosphate goes down the drain’.

Phosphoric acid functions as an essential nutrient for all forms of life. Phosphate is critically important in energy metabolism, in genetics, in the structure of cell membranes and the composition of bone. As a work-ing rule, the phosphorus content of all living plants and animals is around one per cent of total mass. So phos-phorus is much more than a trace element.

More than three billion people are presently mal-nourished – the largest number recorded in human his-tory. For many thousands of generations, we humans were largely hunter-gatherers. We moved over the land according to season, gathering fruits, nuts, seeds, edible tubers, eggs and honey. We ate insects and their grubs, shellfish, snakes, lizards, birds, fish and other small animals. The residues from the digestive processes were discharged daily as urine and faeces, and were returned to the soil very close to where the plants grew, or the small insects and animals lived.

About 10,000 years ago, people in central China, the Middle East, New Guinea and the Americas started living in small fixed communities and harvested most of their food from a defined area of land – a garden. Farming had started. In the tropics, farming was usu-ally ‘slash and burn’. The farmers cleared a few acres of rainforest, burnt the timber and planted seeds in the ash. After a few seasons, yields would start to decline through depletion of the nitrate and phosphate nutri-ents. So another patch of forest was cleared and the first area was allowed to regenerate.

Regeneration occurs because trees are deep-rooted and can reach down to the underlying rocks, where bac-teria are busily liberating water-soluble phosphate for their own needs. Fine, hair-like tree roots can then grab a share of this bounty and transport it up into the tree. Leaves and twigs are shed constantly and rot down in the surface soil, releasing nitrate and phosphate. Slow weathering of the rocks on the surface also contributes phosphate.

In the temperate zones, early farmers not only

grew fruits and vegetables but also learnt to herd their animals as valuable sources of food. A young calf can reach a mass of 700 kilograms in about three years from conception, so this steer has removed seven kilograms of phosphorus from the soil. On a modern farm, this amounts to about 78kg of superphosphate. If the ani-mal were to die on the farm, some 20 per cent of the phosphorus would be returned rapidly to the soil, but not the 80 per cent portion in its bones. This miner-alised phosphate – hydroxyapatite - will only be re-leased very slowly by microbiological action.

For several thousand years, the Chinese have re-turned their human wastes to the soil. The early farm-ers in Europe also learnt the fertiliser value of animal dung and human night soil. But they learnt only slowly – garbage dumps and manure heaps were usually close to the houses.

Brown points out that once we started to export food from the farm to feed townsfolk, we set up a vi-cious circle, a positive feedback loop, between the farm and the city. As the cities grew, requiring daily food and water, the demand for these commodities steadily in-creased, requiring larger and more efficient farms. More food then allowed further growth in the city popula-tion: positive feedback. In the past 100 years, London has grown from a few million to 7.5 million, Tokyo from 1.6 million to 34 million. London now imports 80 per cent of its food from overseas – apples from New Zealand, vegetables from Africa and meat from Brazil and Australia. A typical meal travels 3000 kilometres from farm to the Londoner’s knife and fork. And in 2006, more than half the world’s people lived in cities, most of them in mega-cities.

In the first half of the19th century, cities were nox-ious, fever-ridden places, largely because the disposal of human wastes was becoming unmanageable. A truly brilliant solution emerged: the flush-toilet, connected to a sewerage system with ultimate disposal of the wastes into the ocean. The London model was copied worldwide. It has been remarkably successful in elimi-nating disease.

Along with input of food and water, every city re-quires continuous removal of wastes, now mainly by sewerage systems, waste dumps and cemeteries. This amounts to a steady and largely irreversible loss of phosphate. Note also that modern fertilisers, such as ammonium phosphate, are credited with providing up to 60 per cent of current crop yields.

In 1900, the world population was 1.6 billion. It is now more than six billion. Three factors threatening a future famine are soil erosion, polluted water and a

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critical shortage of phosphate. We do have solutions to the first two problems, albeit at some cost. But declin-ing rock phosphate reserves (the source of superphos-phate) and the continuous losses of phosphate are dif-ferent matters. Brown calculates that the reserves will be exhausted within 85 to 190 years. Steen, (quoted by Brown) arrived at similar figures, 60 to130 years.

Some phosphorus can be recycled through the air, as phosphorus pentoxide in bushfire smoke. Wind-blown soil can move phosphate from one place to an-other, and small amounts can come back from the sea via seabird droppings. These inputs are quite minor compared to the one-way mining of phosphate rock. Phosphate also comes back from the ocean in the fish we eat, but most of this goes straight back to the sea via the city sewers.

Most of the phosphate entering the sea precipitates as a fine rain of insoluble calcium phosphate. The aver-age concentration of phosphate remaining in solution is about 70 micrograms per litre. Each year, some 150 to 200 million tonnes of superphosphate are applied to the land. If equivalent phosphate were to be recovered from the ocean, seawater would have to be processed at the rate of 250,000 cubic kilometres per year. This is an immense volume: more than 70 times the current global consumption of fresh water.

The most immediate action we can take is to return all suitably treated sewage effluent and sewage sludge to farmland, and face up to very considerable costs. Such recycling is being attempted in various ways and places, especially in Europe. A large farm is a unique feature of Melbourne’s sewage treatment at Werribee, and already captures some of the nutrients. There are proposals to divert significant volumes of the effluent to Werribee market gardens, which is highly commendable. But there are problems: people are worried about viruses.

Work is also in progress to improve the quality of the effluent at Melbourne’s Carrum Treatment Works by removing or destroying viruses, bacteria and chemical pollutants, and to provide tapping-points from the exist-ing pipeline to the Gunnamatta Beach discharge point. It would then be possible to return the phosphate-rich effluent to agricultural use on the Mornington Penin-sula. A more recent proposal is to pipe the treated water back to the Latrobe Valley to be used as cooling water for the power stations, to save fresh water.

The EPA (Victoria) approach is to encourage the use of biosolids, while recognising that there are some associated risks. There is a wide range of permitted ap-plications for these sewage by-products, but sometimes the sewage authority cannot provide treatment to the

appropriate level, and sometimes there is a lack of de-termination in finding a suitable re-use opportunity.

Huge quantities of water are used in sewage dis-posal. There has been much experimentation with ‘dry’ toilets, and this technology, using a forced air draft to achieve rapid aerobic breakdown of wastes, has real possibilities. These modern composting toilets are clean and odourless.

About 80 per cent of the cost of our water-based system is in the pipes connecting all the houses to a central treatment plant. With each toilet a separate and isolated operation, the money saved by not having a reticulation system could be used to provide a skilled force of technicians to regularly service the equipment. All toilets could be operated and maintained by a sew-erage authority, which, as now, would have a separate contract with each homeowner. One hundred per cent of the dry nutrients could be recycled for agricultural use, and massive quantities of water would be made available for other uses. In established cities we could change the law and make it legal to collect rainwater from all hard surfaces and discharge it not to the gut-ters but all the way through the sewer pipes to the erst-while sewage treatment plant, where it could be given a clean-up and then used in agriculture.

Slum dwellers in developing countries are finding a possible solution. They are turning positive feedback into negative feedback. It is called ‘urban agriculture’. About one billion city dwellers spend some time each week raising their own food. In Calcutta, 20,000 people farm richly composted old waste dumps and raise carp in tanks charged with dilute sewage effluent. In Lima, they raise guinea-pig meat inside their slum dwellings. In Haiti, people grow vegetables in old, cut-down truck tyres. In booming Shanghai, about one-third of the land within city limits is still used for agriculture, and one million of the 13 million inhabitants still work the land. And use their wastes to fertilise it. further reading: A. duncan brown, Feed or Feedback: Agriculture, Population Dynamics and the State of the Planet. 432 pp. international books, utrecht, the Netherlands

JOHn m. SWAn AO FAA FTSE FrACI is an emeritus professor of monash university with special interests in chemistry, biology, water, the marine sciences and a wide range of environmental issues, ranging from improvements in wool scouring to restoring the seagrasses of Western Port. Post-retirement he has held appointments at the Howard Florey Institute for Physiology and medicine, the Department of History and Philosophy of Science at the university of melbourne, the CrC for Southern Hemisphere meteorology, the Westernport region Water Authority, the Candowie–Lance Creek Catchment management Group and the Victorian Coastal Council. He is a director of the Western Port Seagrass Partnership and chairman of Hallmark Dell Pty Ltd.