Leading stem cell company announces move to Cambridge

Stem Cell Sciences Ltd, a global leader in embryonic stem cell technologies, has announced its intention to create its UK headquarters in Cambridge. It plans to utilise its new location in the East of England to further its aims for expansion and make strategic links to the pharmaceutical and biotechnology companies that are based in this region. Stem Cell Sciences (SCS) is currently based in Scotland, and enjoys strong links with Edinburgh University. The company was initially founded ten years ago on research emanating from the laboratory of Professor Austin Smith, at the Institute for Stem Cell Research in Edinburgh. Professor Smith and Dr Peter Mountford, Chief Executive Officer of SCS, were responsible for filing the controversial ' Edinburgh Patent', which covered the selection and isolation of animal and human embryonic stem cells. SCS now offers a range of products and services based on stem cell science, including specialist media and cell lines for testing drug toxicity, and are currently working on developing embryonic stem cell lines that would be suitable for clinical applications. Since it was established, the company has also acquired research facilities in Australia and Japan, as well as Edinburgh. In an interview with Business Weekly, Dr Tim Allsopp, Chief Scientific Officer at SCS, described the investment in this region as "significant", and also hoped it would lead to opportunities for the company to, "link up with key scientists and academics within the Cambridge community".

SCS will float on the Alternative Investment Market (AIM) next month, and hopes to raise at least £10million from the IPO. This funding stream will allow its expansion into the US, as well as the move to Cambridge. Other stem cell based companies, such as ReNeuron, have enjoyed mixed fortunes since going public but executives at SCS remain highly optimistic about its future and the position of the UK as world leader in the field. - 29/06/05 Dr Ireena Dutta

 

MicroRNAs and cancer

MicroRNAs (miRNAs) are a recently discovered group of small (21-25 nucleotides long), non-coding RNAs that act as negative regulators of gene expression in a range of organisms, including plants. MicroRNAs work via RNA interference complexes (‘RNA-induced silencing complexes’ or RISCs), targeting them to messenger RNAs where they either inhibit translation or direct destructive cleavage [see Meltzer PS (2005) Nature 435, 745-746]. They are known to be involved in the control of key cellular processes such as cellular proliferation and apoptosis. More than 200 miRNAs have been identified in humans, but their precise functions have not been well established. However, three new papers in the latest edition of Nature demonstrate a role for miRNAs in the formation of human tumours.

The first paper reports investigation of a cluster of miRNAs on chromosome 13, the mir-17-92 polycistron, that is present in a region of DNA known to be amplified in forms of human B-cell lymphoma [He L et al. (2005) Nature 435, 828-833]. The researchers compared levels of miRNAs from this cluster in four lymphoma B-cell lines, normal B-cell lines and also five leukaemia and lymphoma cell lines in which the region containing mir-17 is not amplified. It was shown that expression levels of miRNAs from the cluster were high in the lymphoma cells.They also looked at mir-17 expression in lymphoma and colorectal tumour samples, and found significant overexpression in 65% of the lymphoma samples compared with 15% of the colorectal samples; levels of expression were also higher in the lymphoma than colorectal tumours.

To test whether mir-17 contributes to tumour formation, they used a mouse model of human B-cell lymphoma and used a viral vector to transfect animals with the miRNA polycistron. The mice normally develop tumours by 4-6 months, but those in which the miRNAs were overexpressed developed tumours much faster, in an average of 51 days. All had developed tumours within 90 days, compared with less than 30% of control animals transfected with ‘dummy’ vectors. The authors conclude that the mir-17-92 cluster is a potential oncogene.

The second paper reports the use of a bead-based system for miRNA expression profiling, whereby polystyrene beads impregnated with fluorescent dyes were linked to oligonucleotides complementary to the miRNAs of interest. Analysis of fluorescence following passage of miRNAs over the beads revealed the identity and abundance of miRNAs captured on the beads [Lu J et al. (2005) Nature 435, 834-838]. The research team looked at expression of all known mammalian miRNAs in a total of 334 tumour samples. They found that almost all miRNAs were expressed, and that characteristic expression patterns were associated with specific tumour cell lineages. For example, the profiles from colon, liver, pancreas and stomach cancers clustered together, which the authors propose reflects their shared developmental lineage from the embryonic endoderm. These patterns were not reproduced by mRNA profiles based on the expression of 16,000 mRNAs.

It was then decided to compare miRNA expression in human cancer samples and normal tissues; it was found to be generally much lower in the tumour samples than the corresponding normal tissue, leading the authors to hypothesise that global miRNA expression reflects the state of cellular differentiation. They report that miRNA profiling of cell lines showed induction of multiple miRNAs when cells were stimulated to differentiate. They conclude that downregulation or other abnormalities of miRNA expression may contribute to tumour formation and maintenance, and that the use of miRNA expression profiling may prove to be valuable in cancer diagnosis.

The third paper reports that c-Myc, the product of a proto-oncogene commonly dysregulated in human cancers, activates expression of the mir-17 miRNA cluster [O'Donnell KA et al. (2005) Nature 435, 839-843]. The researchers used oligonucleotide arrays to analyse miRNA expression profiles in human B-cells in which expression of c-Myc (a transcription factor) was repressed or normal. Several miRNAs from two clusters, one of which was the mir-17 cluster on chromosome 13, were found to be consistently upregulated in cells with normal levels of c-Myc. Using different cell lines, they found that expression of the mir-17 miRNAs was repressed in the absence of c-Myc and restored by its presence. Immunoprecipitation experiments suggested that c-Myc binds to a specific region just upstream of the mir-17 locus.

To investigate the effects of c-Myc induction of the mir-17 region miRNAs, the team examined expression of the E2F1 gene, which is known to be induced by c-Myc and thought to be a target of the miRNAs in question, miR-17-p and miR-20a. They used human HeLa cells transfected with constructs that bind to and inhibit the miRNAs, and found that this increased E2F1 protein (but not mRNA) levels four-fold. Conversely, the use of a construct overexpressing the mir-17 cluster in HeLa cells produced a two-fold decrease in E2F1 protein (but not mRNA) levels. The authors conclude that c-Myc targets miRNAs, and that the mir-17 region regulates c-Myc mediated cellular proliferation by affecting E21F expression levels.

Comment: These papers investigate different aspects of the role of microRNAs in cancer, but taken together provide a clear demonstration that miRNAs are indeed involved in tumour formation. Commenting on the research, Dr Paul Meltzer, of the US National Human Genome Research Institute, said: "These studies change the landscape of cancer genetics" (see BBC news report). The precise nature of this involvement may prove to be highly complex, and it is likely that a great deal of research will be necessary to elucidate the pathways and mechanisms by which miRNAs work in normal and cancerous cell development. However, besides basic cancer research, some of the potential applications of this research are already clear, such as improved diagnostic and perhaps prognostic tools. – 28/6/05 Dr Philippa Brice

 

EPO to stop making decisions on stem cell patents

Alain Pompidou, President of the European Patent Office (EPO), has said that the EPO will, for the time-being, stop making decisions on patent applications involving human embryonic stem cell technologies [Schubert, S. Nature 435:720-1]. The announcement, made during a presentation of the EPO’s 2004 Annual Report, did not include an expectation of when this decision will change. Pompidou gave the reason that “…there are too many ethical aspects that have not been resolved at the political level". This may refer to the fact that the European Commission is still in the process of deciding whether or not to fund embryonic stem cell research under the upcoming 7th Framework Programme.

It is reported that three applications involving embryonic stem cells are currently being considered by the EPO. One is before the EPO’s technical appeal board with a decision expected in October. If this board cannot settle the case on technical grounds it could be sent to the Enlarged Board of Appeal, EPO’s highest appeals board. If so, any decision made by the Enlarged Board may set a precedent about the patentability of inventions involving human embryonic stem cell technologies. Other countries already patent such inventions, such as the United States and South Korea, and European scientists worry that refusing patents on these inventions will cause economic repercussions. The UK Patent Office (UKPTO) has stated in its guidance, Inventions Involving Human Embryonic Stem Cells, that, in regards to human embryonic pluripotent stem cells, it “…is ready to grant patents for inventions involving such cells provided they satisfy the normal requirements for patentability". The UKPTO describes pluripotent stem cells as "...not hav[ing] the potential to develop into an entire human being". Processes for obtaining stem cells from human embryos and human totipotent cells (those that do have the potential to develop into a human being) are not patentable. - 15/6/05 Dr Susan Wallace

 

Epigenetic stability of human embryonic stem cell lines

Early embryonic development involves the sequential expression of a number of different genes, directing cells towards specific pathways that eventually lead to the formation of different cell types and tissues. A key way in which gene expression is regulated is through epigenetic mechanisms. These mechanisms, such as DNA methylation or histone modification, work by altering DNA and its associated proteins without changing the DNA sequence. For example, methylation of the nucleotide cytosine results in the physical displacement of transcription factors that normally bind to the sequence and the compaction of chromatin around the site, which together lead to gene silencing. Imprinted genes are subject to regulation by epigenetic modifications, and are expressed from either maternally or paternally inherited chromosomes. Imprinted domains on the two parental chromosomes have different epigenetic modifications that control expression from each one. These genes are expressed in the developing embryo and placenta, and in the prenatal and postnatal brain, and are involved in the control of normal growth and development. To date around seventy imprinted genes have been identified, and imprinting defects can cause several neurological and developmental disorders such as Prader-Willi and Beckwith-Wiedemann Syndromes. It has also been suggested that individuals born via assisted reproductive technologies may also have a higher incidence of imprinting-related disorders.

Human embryonic stem cells are derived from the blastocyst stage of embryonic development and could therefore be subject to epigenetic instability or variation, resulting in the inappropriate expression of imprinted genes. A recent paper in Nature Genetics has examined the epigenetic stability of six imprinted genes in cultured human embryonic stem (hES) cells. The researchers at Cambridge University cultured four hES cell lines to middle or high passage under standard conditions and used RT-PCR to detect the presence of specific transcripts from six imprinted genes. The four cells lines carried polymorphisms between the maternal and paternal alleles of these genes, and therefore direct sequencing of the RT-PCR products was able to determine whether the transcripts were as a result of maternal or paternal expression. The imprinted genes, IGF2, IPW and KCNQ1OT1, are normally paternally expressed, and were found to be strictly monoallelically expressed in the four lines. The maternally expressed genes, SLC22A18, NESP55 and H19, were also investigated. Expression of SLC22A18 and NESP55 were predominantly monoallelic with low expression of the paternal allele. H19 was initially monoallelically expressed, but biallelic expression increased during prolonged passage (p66-76). The non-imprinted gene TSSC4 was studied as a control and was found to be consistently biallelically expressed.

The epigenetic mechanisms responsible for imprinting were also investigated. Two differentially methylated regions (DMRs), linked to the genes KCNQ1OT1 and SNRPN, normally have maternal-specific methylation that is acquired during gametogenesis. Bisulphite sequencing was used to analyse the methylation status of these key imprinting control regions. The investigators detected equal proportions of fully methylated and unmethylated DNA, which was consistent with the maintenance of normal differential methylation. Similar analysis of the paternally methylated H19 DMR also identified differential methylation. The H19 promoter region of the paternal allele is not normally methylated during gametogenesis but after implantation. It was found that all the cell lines analysed possessed differential methylation at this region, but the levels were more variable than for the primary DMRs. Previous work on mouse embryos has often demonstrated inappropriate regulation of H19, with altered methylation at the DMR. The investigators suggest that as methylation appears to be retained in the human cell lines alternative mechanisms, such as chromatin modification, may be circumventing the germline methylation signal. The authors conclude that although further work is required on the methylation status of imprinted genes and their expression, this study demonstrates that hES cell lines are epigenetically stable at imprinted regions and that epigenetic status should not act as a barrier to the use of these cells for therapeutic purposes.

Comment: This paper goes some way to address the concerns regarding the epigenetic stability of hES cell lines, and the potential impact of this on their suitability for therapeutic use. Previous research on sheep and mouse embryos, and mouse stem cells has shown that they are prone to epigenetic variation and the loss of normal imprinted gene expression, when cultured in vitro. This study demonstrates that at low passage hES cell lines are both appropriately imprinted and epigenetically stable. However, the investigators also highlight the fact that methylation profile does not always relate to normal gene expression, and that both must be studied for a definitive assessment of epigenetic stability during development. Additionally, this study only examined the expression of six imprinted genes, a small proportion of the total number of imprinted genes that have been identified to date. However, this study does establish hES cells as a potential model in which to study the expression of imprinted genes and early development and also indicates that epigenetic stability should not be an obstacle to their use in stem cell therapies. - 7/6/05 Dr Ireena Dutta

The full research article can be found at Rugg-Gunn, P.J. et al (2005) Nature Genetics 37 585-587 (requires full text access).

 

South Korean cloning researcher to open stem cell bank

Hwang Woo-suk, who with his researchers created the first patient-matched embryonic stem cell lines, has announced that he plans to open a stem cell bank in Korea. In an interview with the Associated Press [Kim. J., Washington Post, 1 June 2005], Hwang discussed his plans for a stem cell bank to consolidate access to existing stem cell lines. He envisages a bank where researchers from around the world could come to seek out stem cells that would match a patient in need, a process like that used to find organ transplants. He expects the bank to open as early as later this year; management of the bank would be given eventually to an international agency. The Korea Times reports [Kim, T. Korea Times, 25 May 2005] that the Korean government will be supporting Hwang with an increase in his research budget and a new research facility at Seoul National University.

Hwang and his colleagues announced their groundbreaking work creating genetically matched stem cell lines in May 2005 [see Hwang, W.S. et al, Science, 19 May 2005]. He and his team derived 11 stem cell lines that genetically matched the patients from whom skins cells used in the procedure were taken. The patients suffered from disease or spinal cord injury. Last year, Hwang and his colleagues announced they had cloned a human embryo [see PH GU newsletter item February 2004]. Now he plans to move to the next phase of his research plans. He told the Korea Times, “We already have some globally organised research teams. After concluding the worldwide framework this year, we will push for more progress. I hope to lower the curtain of the first act (of the stem cell play) by as early as next autumn.” The Associated Press reports that he next plans to move into growing specific tissues and organs from stem cells.

One international collaboration being planned is with Dr Douglas Melton at the Harvard Stem Cell Institute in Harvard, Massachusetts, according to a Bloomberg report [2 June 2005]. Melton is seeking to use embryonic stem cells in treatments for diabetes. He has already isolated 17 stem cell lines from unneeded IVF embryos, using private funding. The Massachusetts legislature recently overrode a veto by the state’s governor of a state law that allows somatic cell nuclear transfer or therapeutic cloning, as long as the research has ethics approval and does not result in the cloning of a human being. This puts Massachusetts, according to Senator Edward Kennedy, “…at the forefront of science, innovation and discovery.” The report states that a link with Harvard might help with Hwang’s goal of creating the stem cell bank in Korea. - 6/6/05 Dr Susan Wallace

 

The President’s Council on Bioethics reports on alternative sources of pluripotent stem cells

The body that advises the President of the United States on ethical issues surrounding biomedical research has published a report on stem cell biology and alternatives to the use embryonic cell lines. The President’s Council on Bioethics was created by President Bush in 2001 and is made up of leading academics in the fields of law, ethics, policy and medicine from a number of US universities. The Council has been investigating methods of producing stem cells that are pluripotent and genetically stable but do not involve the creation or destruction of human embryos. They specifically evaluated the scientific and ethical strengths and weaknesses of four approaches involving obtaining stem cells from four sources: dead early stage embryos; living embryos by non-destructive biopsy; bioengineered embryo-like artefacts; and reprogrammed adult somatic cells.

The report entitled, Alternative Sources of Pluripotent Stem Cells, was unable to conclude which, if any, of these particular approaches would provide a viable alternative to the use of embryos for the derivation of pluripotent stem cell lines mainly due to the lack of scientific and technical evidence. However, it did form preliminary conclusions on the approaches in terms of their ethical acceptability. It found that the derivation of cells from dead embryos was “ethically acceptable for basic investigation in humans, provided that stringent guidelines…are strictly observed”. The extraction of material from living embryos was found to be ethically unacceptable, and it concluded that, “we should not impose risks on living embryos destined to become children for the sake of getting stem cells for research”. The derivation of cells from engineered biological artefacts was not found to be ethically acceptable at this time, although further research in animal models may change this view. Obtaining cells from adult somatic cells was also ethically acceptable to the Council. The report conceded that some Council members might have felt that the “quest for alternative sources of stem cells is misguided” and that existing methods utilising embryos should continue to be used. But it also endorsed the four alternative options as “worthy of further public discussion” and called for further research in the area.

The composition of the Council has proved to be controversial following the departure from it last year of some members supportive of embryonic stem cell research. Critics of the Council have accused it of pursuing a neoconservative political agenda that is aligned to the Bush administration, rather than reflecting a range of bioethical viewpoints but its Chair Leon Kass has maintained that the Council is “easily the most intellectually and ethically diverse of the bioethics commissions to date”, and that “no one who has attended any of our meetings or read the transcripts can believe that we do anything but serious and careful work, without regard to ideology, partisan politics or religious beliefs”. –27/5/05 Dr Ireena Dutta

 

Funding boost for experimental medicine and translational research

A new funding programme for experimental medicine has been announced by the UK Clinical Research Collaboration (UKCRC). The UKCRC is made up of a number of commercial, governmental and research organisations and aims to improve the environment for clinical research in the UK. As part of this goal it has allocated £74million to support experimental medicine and the translation of scientific research into clinical application. The Medical Research Council, the Wolfson Foundation, the Wellcome Trust, the Department of Health and the Scottish Executive Health Department are acting together as partners in the UKCRC to provide these funds.

Almost half of the available funds have been allocated to the establishment of new clinical research facilities that will enable universities and hospital trusts to work together on patient-focused research. A further £5million will be dedicated to the development of new treatments in clinical settings.

As part of the package, the MRC is also committing £15million for experimental medicine research, and has issued a call for proposals in this area. The proposals should involve human participants either from the outset or at some stage of the study, and should also seek to translate the research into clinical practice in the short to medium term. It is specifically seeking to fund collaborative research between basic and clinical scientists and industry with an emphasis on:

• “Proof of concept” studies designed to explore pathophysiology, gain early evidence that an intervention has an effect and/or investigate mechanism of action.
• Early evaluation of novel diagnostic methodologies
• The characterisation of intermediate phenotypes or surrogate markers of disease progression or response to treatment
• Investigation of new technologies and technology assessment

Expressions of interest should be submitted by the 17th June 2005, and further details of the call can be found at the MRC website. – 26/5/05 Dr Ireena Dutta

 

US House of Representatives votes to repeal stem cell research restrictions

The US House of Representatives, by 238 to 194, has passed a bill that would repeal the current restrictions on federal funding for human embryonic stem cell (hESC) research, according to the Washington Post [25 May 2005]. However, it will still need approval by the US Senate and the President, who has already stated he will not sign the bill into law. The Stem Cell Research Enhancement Act of 2005 [H.R.810.EH], would allow researchers to apply for federal money to remove hESCs from surplus embryos from in vitro fertilisation treatments, with the consent of the donor couple and without financial inducements to donate.

Currently, US researchers can only use federal money to conduct hESC research on stem cell lines that existed on 9 August 2001, the date President Bush announced an executive order limiting federal funding of hESC research. Critics of the current policy argue that limiting research to ‘approved’ stem cell lines, many of which are contaminated by animal products and therefore cannot be used in human experiments, is seriously hindering medical research in the country. They argue that the United States must be active in this research, in order to develop treatments for illnesses such as Parkinson’s disease and cardiac disorders, as well as to maintain a competitive position for US universities and companies involved in this field. However, many in Congress oppose the bill and a relaxation in the federal policy, such as Congressman Henry J Hyde, a Republican from Illinois, who believes that if it passes, “…taxpayers’ dollars are going to be spent for the killing of innocent human life.”

This vote does not signal the end of the process of attempting to change the current regulatory position in the US. The US Senate has yet to vote on their version of the bill, although indications show that that vote will take place soon. If both the House and the Senate agree a version of the bill, it will go to the President, who has said he will veto the measure, his first veto since taking office. The House of Representatives does not currently have the necessary votes, two-thirds of their membership, to override a veto. The fact that a large number of Republicans joined their Democratic counterparts to pass this bill does show that there is a shift in attitude in favour of hESC research, but researchers may need to continue to rely on private funding, which avoids the federal restrictions, for the time-being.

In addition to the hESC bill, the House also passed the Stem Cell Therapeutic and Research Act of 2005 [H.R.2520.EH], which authorises federal money to be spent on the collection and banking of unused umbilical cord blood, from which foetal stem cells could be sourced for research purposes. This much less controversial bill passed easily, 430-1. This bill will also need to progress through the Senate and then to the President for signature, but it should face much less opposition.However, hESC researchers have noted that foetal stem cells have only been shown to differentiate into a limited number of cell types, unlike hESCs which can change into any cell type, and therefore the therapeutic applications may be limited. - 25/5/05 Dr Susan Wallace

 

Calls for routine genetic screening of IVF embryos

At the Sixth International Symposium on Preimplantation Genetic Diagnosis held in London last week, society president Dr Yury Verlinksy called for all embryos created by IVF to be checked for genetic abnormalities prior to implantation in the womb. Dr Verlinksy, of the Reproductive Genetics Institute in Chicago, presented results on the outcomes of pregnancies in 709 women who had IVF, reporting that the use of PGD increased the chance of a live birth from 11% to about 80%, due to fewer miscarriages and better foetal implantation rates. He commented that "40-70% of all embryos are somewhat abnormal and this is human nature" , and therefore proposed that all IVF embryos should be checked in order to maximise the success rate of the procedure, saying that the additional expense of PGD could be justified by the reduced need for further cycles of IVF.

He also said that couples undergoing IVF should be allowed to select the sex of the embryo to be implanted, and was supported in this assertion by IVF pioneer Professor Robert Edwards, who commented: "We need politicians to realise how far PGD has come, and it has to be paid for by the health service". However, critics condemned these proposals as unethical; a spokesman from pro-life charity LIFE said: "Just because something is scientifically possible it does not mean we should do it…My fear is that scientists are deriving this without recourse to ethics and public opinion" (see BBC news report). The Department of Health reportedly said the safety, clinical effectiveness and relative health benefits of PGD would need to be assessed before any decision about widespread provision could be made. – 23/5/05 Dr Philippa Brice

 

Patient-specific stem cells derived for the first time

A team of South Korean scientists have developed the first human stem cell lines derived from specific patients. The team, which was led by Professor Woo Suk Hwang, was also the first in the world to create human embryos by cloning in 2004 (see previous newsletter item). Unlike the announcement of the cloning of the first human embryo in the UK, made by researchers in Newcastle, this discovery has been published in a prominent scientific journal.

Publishing a summary of their results in Science Express, the researchers described the creation of eleven human embryonic stem cell lines by somatic cell nuclear transfer. Nuclear material was obtained from the skin cells of patients with various diseases or injury, and injected into donated oocytes from which the nuclei had been removed. The cell lines that were developed were reported to be pluripotent, chromosomally normal, and genetically identical to the original patient, even if they had been grown on genetically-unrelated human feeder cells. Comparison of the Major Histocompatibility Complex (MHC) of each of the lines with the original patient from which the nuclear material was taken demonstrated that they were also immunologcally compatible. This indicated that these cells could eventually be used in transplantation, to replace damaged tissues, without the risk of rejection. However the authors also highlight that additional studies are required to investigate the genetic stability of these lines over time and how to sustain them without the need for animal-derived components in the culture media. Further research is also need to develop appropriate methods for directing the differentiation of these cell lines into specific types of tissue or cells with particular functions that would be both clinically safe and useful for patients.

The safety issues surrounding the therapeutic use of stem cells have also recently been raised in a publication by a number of leading researchers in the field. Writing in the British Medical Journal the authors, including Dr Stephen Minger of King’s College London, state that the premature and unregulated implementation of stem cell therapy using poorly sourced cell lines could put patients at risk of contracting viral or prion diseases. This situation should be avoided in Europe with the implementation of the EU directive on cells and tissue, which will impose stringent quality standards on all clinics and laboratories but many countries still do not have relevant legislation governing this particular field.

However despite the complex technical and clinical issues that still need to be addressed it is clear that the scientific advances made by the Korean team have moved forward the possibility of using stem cell-based therapies as treatments for a range of conditions such as Parkinson’s disease, heart disease and diabetes. Commenting on the breakthrough to BBC News, Professor Roger Pedersen, of the Cambridge Stem Cell Institute, said “The work provided ample evidence for the feasibility of replacing the genome of a human egg with that of an adult body cell”. Professor Ian Wilmut of the Roslin Institute added, "These new observations make a very significant and important step forward toward the use of cells from cloned human embryos for research and therapy." – 20/05/05 Dr Ireena Dutta

UK scientists report first cloned human embryo

In a paper submitted to the journal Reproductive and BioMedicine Online (but not yet peer reviewed or accepted for publication), a team of scientists from the Newcastle Fertility Centre at Life and Newcastle University led by Professor Alison Murdoch report the creation of human blastocysts following heterologous nuclear transfer of DNA from human embryonic stem cells into a human oocyte. A total of 36 oocytes from 11 women were used; three clones survived for three days and one for five days. The researchers said that the speed with which oocytes were collected and manipulated was a key factor in the survival of the clones; those that survived in culture had been created within an hour of oocyte harvesting, and within 15 minutes for the one that survived for five days.

The Human Fertilisation and Embryology Authority (HFEA) granted a therapeutic cloning licence to the Newcastle team in August 2004 (see newsletter item), for the purpose of increasing knowledge about the development of embryos as the foundation for further development in the treatment of serious disease. – 20/5/05 Dr Philippa Brice

 

Details of UK Stem Cell Initiative announced

The Government has revealed details of the composition and remit of the UK Stem Cell Initiative (UKSCI) first announced in the Chancellor’s Budget speech earlier in the year. The UKSCI will undertake a high-level review in order to formulate a ten-year vision for stem cell research in the UK. This will involve public and private sector stakeholders, and aims to create a platform for coordinated research funding from both these sources.

The Initiative is chaired by Professor Sir John Pattison, former head of research and development at the Department of Health. Its membership includes the heads of the MRC, BBSRC and Wellcome Trust as well as executives from the companies Stem Cell Sciences and Smith and Nephew. It also includes representatives from the newly established UK Stem Cell Foundation formed by Professor Sir Chris Evans. The UKSCI’s specific goals will be to:

• To develop a ten-year vision for UK stem cell research, which seeks to make the UK the most scientifically and commercially productive location for this activity over the coming decade, and which commands the support of public and private research funders, practitioners and commercial partners.
• To present a costed plan to Government and business for implementation over 2006-2015, to inform future public spending reviews and private sector investment planning.
• To identify options for better coordinating and leading UK stem cell research and commercial translation in the coming years.
• To report back to Government (DTI, Department of Health, HM Treasury) by Pre-Budget Report 2005

The Initiative forms part of the Government’s continuing commitment to science and technology in the UK, and builds on the strategy outlined in the Science and Innovation Investment Framework published last year. - 19/5/05 Dr Ireena Dutta

 

Plans for new Asian stem cell network

A group of scientists from countries in the Asia-Pacific region have agreed to form a network to promote collaboration in the field of stem cell science. As reported in Nature, the scientists from Japan, China, Hong Kong, Taiwan, Singapore, South Korea, and Australia believe that the more relaxed regulatory environments in these countries will help them avoid some of the obstacles faced by researchers in Europe and the US. Many breakthroughs in human embryonic stem cell research have occurred in South East Asia, and legislation governing this work appears to be more uniform across the region compared to the current situation in Europe. The more liberal attitudes in this area also contrast to the US, which has imposed a ban on the federal funding of human embryonic stem cell research. The Asia-Pacific Stem Cell Network will aim to encourage collaboration and exchange students and host scientific meetings. - 9/5/05 Dr Ireena Dutta

 

US National Academies release guidelines for embryonic stem cell research

A committee of experts set up by two of US National Academies’ constituent members, the Institute of Medicine and the National Research Council, have announced the release of a report, “Guidelines for Human Embryonic Stem Cell Research” [Holden C et al, Science (2005) 308, 611]. It includes guidelines that are “…intended to enhance the integrity of privately funded human embryonic stem cell research by encouraging responsible practices.” The report notes that there is a perception that some aspects of hESC research are unregulated. There are rules for all types of research that is funded by the US federal government, as well as other requirements that would apply to hESC research, but no federal regulations designed specifically for this type of work. As the Washington Post notes, the rules that were imposed by President Bush in 2001 focus on which cells can be used in research but little about what can be done with them [Weiss R, Post 27/04/05]. With the increase of private money becoming available for hESC research, as a way of avoiding the restrictions on federally funded research, the hESC research community has recognised the need for a set of voluntary guidelines [Holden C, Science (2004) 306, 586].

The guidelines cover all derivations of hESC lines and all research using hESCs from donated unused embryos from IVF treatments, embryos made specifically for research using IVF and somatic cell nuclear transfer. They do not cover non-human stem cells. The report lists three categories of research applications: accepted research, research that needs additional review before it is permitted, and research that should not be permitted. Into this last category falls the culturing of embryos for longer than 14 days or until the formation of the primitive streak, whichever occurs first; introducing human stem cells into nonhuman primate blastocysts or introducing any embryonic stem cells into human blastocysts; or allowing any animal into which hESCs have been placed to breed. All other types of research will be considered.

The report recommends a dual system of oversight of the research. Decisions on whether research should take place would be devolved to the level of the institution conducting the research. All institutions that conduct hESC research should create and host an Embryonic Stem Cell Research Oversight (ESCRO) committee, which would be responsible for reviewing hESC research proposals. It should include both lay and expert members. ESCRO committees would not replace institution review boards (IRBs), the US equivalent of research ethics committees, but would “…provide an additional level of review and scrutiny warranted by the complex issues raised…” by this research. At a national level, the report recommends the creation of a body to review the guidelines periodically to see if they are adequate and are taking into account new advances in the field. The national body would not interfere in decisions on individual research proposals. Other recommendations include ensuring the ethical procurement of donor oocytes and embryos; that informed consent procedures are in place; that no fees are paid for donations for research purposes, except for payment of direct expenses as a result of a procedure; and that uniform tracking procedures are put in place for the distribution of cells. In order to ensure that researchers and institutions follow these guidelines, the report recommends that ESCROs, IRBs, funding bodies and journal publishers should require evidence of compliance. - 4/5/05 Dr Susan Wallace

 

Standardized microarrays show promise

Three new reports published in the latest edition of Nature Methods agree that the use of microarrays can yield more reproducible results than previous analyses have suggested, provided that standardized protocols and data processing are used. Microarrays are platforms that allow the simultaneous analysis of expression from thousands of genes, allowing researchers to identify patterns of gene expression that are associated with specific tissues and diseases. They are already being used in clinical trials for use in determining the prognosis and hence treatment options for breast cancer patients.

A study led by the US National Institute of Environmental Health Sciences (NIEHS) funded Toxicogenomics Research Consortium, comprising seven different centres, to assess the causes of variation between gene expression experiments and different microarray platforms has been running since 2001.These researchers report that using a standardized process led to more consistent results, and that using commercially manufactured microarrays made results more reproducible [Bammler T et al. (2004) Nat Methods 2, 351-356]. Dr Brenda Weis, one of the authors of the report, commented: "So far, gene expression data have been very useful in understanding diseases and biological processes…But if we standardize protocols the knowledge we gain from microarray studies can be used to improve clinical practice", adding: "If microarrays are to be used effectively in the clinic to diagnose patients and design patient-tailored therapies, they will need to be like any other clinical tests; they will need to be standardized" (see NIH press release).

A further two studies lend weight to these conclusions. One compared gene expression between two microarray platforms and using different experimental treatments, and concluded that biological treatment had a far greater overall impact on measured gene expression than the use of different platforms [Larkin JE et al. (2005) Nat Methods 2, 337-344]. The second compared microarray analysis data from ten different laboratories generated using identical RNA samples on three different platforms. This group found that different labs using the same RNA and the same microarray platform could produce significantly divergent data; but that the “best-performing” laboratories produced fairly consistent results [Irizarry RA et al. (2005) Nat Methods 2, 345-350]. Taken together, these results are encouraging endorsements of the potential value of microarrays in harnessing genomic information for clinical benefit. – 5/5/05 Dr Philippa Brice

 

Accuracy of Revised Bethesda Guidelines for HNPCC diagnosis

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most common form of familial colorectal cancer and accounts for 1-3% of all colorectal tumours. It is diagnosed following established guidelines, the most recent version being the Revised Bethesda Guidelines for HNPCC (Lynch Syndrome) and Microsatellite Instability [Umar A et al. (2004) J Natl Cancer Inst 96, 261-268]. These guidelines update the original Bethesda Guidelines of 1997 on testing individuals with apparent HNPCC for microsatellite instability, or MSI. This is a genetic feature of tumours that have lost DNA mismatch repair (MMR) activity, mostly due to mutations in the MSH2 or MLH1 genes, although additional genes can also be involved. Such mutations generally cause abnormal MSH2 or MLH1 protein expression, which can be detected by immunostaining.

The purpose of testing for HNPCC is to identify individuals in whom colorectal cancer has arisen due to inherited, strongly disease-predisposing mutations. A diagnosis of HNPCC has implications for the individual’s family, who may then elect to be tested for the presence of the familial mutation and, if found to be carriers, opt for increased levels of medical surveillance or preventative treatments. A new study published in the Journal of the American Medical Association reports on the efficacy of the revised Bethesda Guidelines as a testing strategy for the detection of MSH2/MLH1 gene carriers. The guidelines cover two types of test. Since MSI is present in more than 90% of HNPCC associated cancers, MSI testing to identify the presence of abnormal microsatellite sequences in colorectal tumour samples is a useful method for identifying patients in whom genetic testing for HNPCC is appropriate. However, immunostaining for abnormal MSH2 or MLH1 protein expression is also useful; some tumours with MSH2 or MLH1 mutations do not display MSI.

In this multi-centre Spanish study, researchers compared the performance of both methods, as well as the selection of patients based on the Bethesda Guidelines, for identifying carriers of MSH2 or MLH1 germline mutations [Pinol V et al. (2005) JAMA 293, 1986-94]. They looked at data from a total of 1222 patients with newly diagnosed colorectal cancer between 2000 and 2001. Patients were tested for both MSI and absent protein expression detected by immunostaining; all those who were found to have positive results for either test were then tested for germline MSH2/MLH1 mutations. In all, 287 patients (23.5%) fulfilled the revised Bethesda guidelines for MSI testing, and of these 91 had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) and/or loss of protein expression (n = 81). Germline testing identified 11 mutations in either MSH2 or MLH1 genes.

Statistical analysis was used to evaluate the performance of screening strategies based on microsatellite instability testing and/or protein immunostaining, either directly or through previous selection of patients according to the revised Bethesda guidelines. A cost-minimization analysis was also performed to establish the most efficient strategy, using set costs of €100 (US $130), €200 (US $260) and €2400 (US $3120) for microsatellite instability testing, MSH2/MLH1 immunostaining and MSH2/MLH1 genetic testing, respectively.

The revised Bethesda guidelines were found to be the most discriminating set of clinical parameters for identifying patients at risk of HNPCC. Clinical selection of patients according to these guidelines followed by either MSI analysis or protein immunostaining was found to be more cost-effective than any of these approaches performed directly, with estimated costs per mutation detected of €11989 or €10644 for MSI or immunostaining respectively, compared with €32140 and €37956 for the use of these techniques without pre-selection of patients according to the Bethesda criteria. Both microsatellite instability testing and immunostaining were found to be highly accurate strategies for the identification of MSH2/MLH1 gene carriers, and equivalent in terms of cost-effectiveness. Given that immunostaining is “more available than DNA analysis in a clinical setting”, the authors propose that the use of this technique rather than MSI testing may help to identify a larger proportion of patients with HNPCC.

Comment: Other reports have found MSI testing and immunostaining to be equally effective approaches for HNPCC mutation screening, but some have found MSI superior. This study focused only on mutations in the two most common HNPCC associated genes, and not other genes (MSH3, MSH6, PMS1 and PMS2). However, as observed in an article accompanying the research report, including antibodies against the corresponding proteins in immunohistochemical analyses could further increase diagnostic efficacy [Vasen HF and Boland CR (2005) JAMA 293, 2028-30]. Ideally, a more comprehensive study should be performed to determine whether one method is genuinely better than the other. However, the key question for these researchers was the performance of the Bethesda guidelines and they were clearly found to be effective, irrespective of the testing method used. This provides a strong validation of the guidelines and means that clinicians should apply them to all cases of colorectal cancer, and have access to at least one screening method, in order to maximise the detection of HNPCC. – 5/5/05 Dr Philippa Brice

Insulin-producing cells obtained from neural stem cells

Researchers at Stanford University have reported on the creation of glucose-responsive insulin-producing cells derived from an adult neural stem cell line. Publishing their results in PLoS Medicine, the group investigated the signals that regulate in vivo islet development and their effect on brain-derived human neural progenitor cells.

Pancreatic islet cells and neurons display a number of similarities despite their different origins, including a shared set of developmental regulators. For some invertebrates such as Drosophila neurons are the main source of circulating insulin, and although islets are the principal source in humans it has been demonstrated that insulin gene transcription still occurs in the vertebrate brain. Much research has been conducted on the stimulation of neural differentiation from embryonic stem (ES) cells, and these methods have also been adapted to produce insulin-producing cells (IPCs). This paper describes strategies for developing IPCs directly from human neural stem cells.

The investigators established that restricting the glucose content of the culture media normally used to maintain progenitor neural cells could direct them to follow a developmental path towards becoming insulin-expressing islet cells. They also identified Retinoic Acid (RA) as a factor that promoted the development of IPCs from neural cells. RA normally acts through the Hedgehog (Hh) signalling pathway and recent studies have shown that Hh signals control the development of embryonic pancreatic islets in vivo. However, in contrast to the response of ES cells, this study demonstrated that RA does not stimulate Hh signalling in neural progenitor cells, and it was in fact this absence of Hh signals that stopped neural differentiation and allowed the cells to follow a path towards being IPCs. The researchers also established that the IPCs produced were able to respond to changes in glucose level. By grafting IPCs into mouse models and monitoring their insulin levels during fasting and after challenge with glucose, they determined that the cells were able to respond to the challenge in vivo by releasing insulin. They also monitored the graft sites for a month after transplantation and were able to confirm that the IPCs had survived, remained undifferentiated and had not become tumorogenic.

Recent news stories have raised the possibility of using islet transplantation as a therapeutic model for the treatment of diabetes, and the shortage of cadaveric donors has also focused interest on the development of alternative sources of replacement tissue. These results advance the prospect of insulin-producing cells being grown in vitro and used for transplantation. However the researchers themselves highlight the fact that there are still many obstacles that need to be overcome before this can be applied in patients. For example the IPCs they were able to produce were not actually mature pancreatic islet beta-cells, although they did have similar functionality. This study did not fully demonstrate that it had recreated the normal glucose stimulus-insulin secretion mechanism possessed by pancreatic islets, and the diabetic mouse models used were not comparable to the clinical manifestation of diabetes in humans. However, this is the first study that has documented the production of glucose-responsive IPCs from an expandable population of human stem cells. As the methodology used extra-cellular factors rather than manipulating genes it could potentially form the basis for developing a renewable source of replacement islets from a range of human stem cells, including neural and ES cells. - 28/4/05 Dr Ireena Dutta

The full research article can be found at Hori, Y. et al (2005) PLoS Medicine 2, 347-356.

 

Ethical issues under the EU's Seventh Framework Programme

The European Commission has released a memo explaining its approach to ethical issues in funding projects under the proposed Seventh Framework Programme (FP7). This was prompted by questions of how controversial research, such that involving embryonic stem cells, will be considered under FP7. The Commission cites two statements in its FP7 proposal. Recital 25 reads, “Research activities supported by this Framework Programme should respect fundamental ethical principles, including those reflected in the Charter of Fundamental Rights of the European Union. The opinions of the European Group on Ethics in Science and New Technologies are and will be taken into account.” Secondly, Article 6 states, “All the research activities carried out under the Seventh Framework Programme shall be carried out in compliance with fundamental ethical principles.”

As for human embryonic stem cell research, the memo reiterates how funding is conducted under the current FP6 programme. It confirms that the European Union (EU) will not fund any research “…that involves human reproductive cloning, the creation of embryos for research (or therapeutic cloning) or any research that would alter the human genetic heritage.” The EU will not fund research in the Member State that is illegal in that State and funding priority is given to projects involving adult stem cells. Funding is available for projects that involve deriving and using human embryonic stem cells (HESC) from embryos ‘left-over’ from in vitro fertilisation procedures. The donors must have given explicit consent for their embryos to be used in research. However, the Commission notes that very little of the FP6 budget has been spent on this type of research. Only two projects have been funded, totalling approximately €500,000 and only 0.002% of the FP6 budget. On the other hand, the Commission is eager to fund the set up of a European registry of existing HESC lines, along the lines of the registry at the US National Institutes of Health. The Commission supports such a registry as it, “…would allow an ethical tracking of existing HESC lines in Europe and their optimal use.” While proposals have been received, they have been judged to be of ‘insufficient quality’ and the call for proposals has been reopened.

The memo does not indicate how or if it will fund HESC research under FP7. The European Parliament has already entered into this debate by passing a resolution in March 2005 calling for the specific exclusion of 'human cloning' from funding under FP7 and for embryonic stem cell research to be funded by the national budgets of Member States in which this research is legal and not by the EU (see PHGU newsletter article earlier this month). The Parliament also believes that EU funding should be focused on alternatives to HESC research, such as adult stem cell and umbilical cord stem cell research. A timeline on the FP7 website shows that there will be further discussions regarding FP7 before its launch at the end of 2006. - 26/4/05 Dr Susan Wallace

 

European Commission announces plans for Seventh Framework Programme

The European Commission has announced its plans for the Seventh Framework Programme (FP7), the EU's instrument for funding research and development. The Commission's plan will now be treated by the Codecision process of the European Parliament and the Council of the European Union. FP7 is scheduled to begin in 2007 and last seven years, until 2013. The budget is 72.73 billion euro and will be organised into four programmes: Cooperation, Ideas, People and Capacities.

More than half of the FP7 budget will be allocated to the ‘Cooperation’ programme, under which cooperative transnational research activities, such as those between universities, industry, research centres and public authorities, will be funded. Nine thematic areas are listed for collaborative research: health; food, agriculture and biotechnology; information and communication technologies; nanosciences, nanotechnologies, materials and new production technologies; energy; environment; transport; socio-economic sciences and the humanities; and security and space research. The European Research Council will set up under the ‘Ideas’ programme. It will fund basic or ‘frontier’ research proposed by individual teams competing at the European level. Under the ‘People’ programme, individuals will be able to apply for training and careers development funding, as well as funding for activities such as researcher exchange programmes. Finally, the ‘Capacities’ programme will focus on improving and strengthening research infrastructures.

The Commission has noted that under FP7 less emphasis will be placed on the mechanisms that will be used to fund projects. Under the Sixth Framework Programme, collaboration was a fundamental requirement for funding submissions, often requiring three of more Member States as participants and a strong emphasis was placed on the use of specific instruments for the delivery of funds. Under FP7, these requirements will be de-emphasised and there will be a wider range of funding mechanisms that can be used when responding to calls for proposals, which should be welcome news for researchers. Also, the Commission's proposal states that "All research activities...shall be carried out in compliance with fundamental ethical principles." This requirement is discussed further in a memo outlining ethical issues within FP7 (see related PHGU newsarticle). - 26/4/05 Dr Susan Wallace

 

California makes slow progress after Proposition 71

Following the Californian electorate’s decision to back the creation of a $3billion public fund to support stem cell research in the state, progress with the initiative has been slower than initially expected.

The campaign for a ‘Yes’ vote on the California Stem Cell Research and Cures Initiative, known as Proposition 71, was led by the business entrepreneur Bob Klein who hoped that the first research grants would be approved by May of this year. But this timescale now looks to be hugely optimistic. The ‘Yes’ campaign raised a number of hopes for new research and possible disease therapies but the California Institute for Regenerative Medicine (CIRM), the agency that was instituted to distribute research funds and provide research facilities, has faced a number of hurdles in its work. CIRM’s main goal is to support stem cell research that would not be funded by the federal government in the US. Currently, regulations limit federal funding for stem cell research to work on seventy-eight human embryonic stem cell lines created before August 2001. However, the ‘approved’ lines have usually been grown on a layer of mouse feeder cells that make them inappropriate for therapeutic use in humans, and many of the cell lines that appear most valuable for research purposes were also created after the 2001 cut-off date. The CIRM is committed to funding the development of new embryonic stem cell lines, either by using surplus embryos from IVF procedures or through therapeutic cloning. As this work must be kept separate from any federally funded research, CIRM may also provide support to build new laboratories and other facilities. Although the new investment into stem cell research has been welcomed by the scientific community, some experts have warned that the an over-emphasis on embryonic stem cells may result in the funding of low quality work in this field, with other important areas of adult stem cell research being ignored.

Others have also questioned the governance surrounding how research grants will be distributed. The CIRM is overseen by a ‘citizens committee’ which includes representatives of the biotech industry and academic institutions that are likely to benefit from CIRM funding. The Institute’s procedures on potential conflicts of interests and accountability have been criticised by a number of state senators, and although CIRM has responded to these, it still faces lawsuits from other opponents who have declared it to be unconstitutional. Some researchers have also voiced concerns regarding the diminishing role of federal government agencies, such as the National Institutes of Health (NIH) in the field, believing that increased availability of state funding could see NIH budgets cut. Commenting in Nature magazine, George Daley, a stem cell researcher at Harvard Medical School said, "I am worried that the willingness of states to take up the slack is going to absolve the federal government of its responsibilities in this area". The Institute hopes that many of the problems it faces will be addressed and resolved when it appoints a President, but with states such as New Jersey, Connecticut, Massachusetts, and Wisconsin all planning or already establishing similar bodies, it seems that these issues that are likely to reappear in the future. – 19/04/05 Dr Ireena Dutta

Stem cell research funding update

The past few months have seen a number of new announcements made concerning funding for stem cell research in the UK and internationally. In March the Department of Trade and Industry announced the allocation of £1billion of funding to the life science and biotechnology sector. This allocation is from the £10billion science budget agreed in the 2004 Spending Review. It furthers the Government’s commitment to science and innovation that was initially outlined in the ten-year investment framework. The new allocation specifically covered areas such as stem cell research and bio-processing. Some of the additional funding will increase the budgets of the MRC and BBSRC, as well as assist UK universities collaborate with business and create new companies to exploit their research.

The EU has also allocated €12billion to a pan-European stem cell research collaboration involving groups in the UK, Sweden, Germany, Italy, France and Finland, which will investigate the therapeutic potential of human embryonic stem cells. However, some of the home nations of the scientists involved, such as Italy and Germany, have restrictive national legislation governing this type of research. This may lead to their representatives within the EU seeking to delay the project, or to remove their scientists from it completely. The confusion over the future of the project follows the recent decision by the European Parliament to change legislation governing the funding of embryonic stem cell research (see earlier story). This change proposes that embryonic stem cell research should be funded from the national budgets of member states where the research is legal and not by the EU. However the resolution has not been adopted by the European Commission and is not specifically mentioned in its recent announcement of the 7th Research Framework Programme. – 22/04/05 Dr Ireena Dutta

New research and development grants available from EEDA

Applications are invited for the new research and development grants, which have replaced the DTI’s SMART awards. The grants are being administered in England and Wales by the relevant regional development agencies. The research grants are available to those seeking to create new businesses, as well as existing small and medium-sized companies. Full details of the application process and guidelines can be found on the East of England Development Agency website. - 21/4/05 Dr Ireena Dutta

 

Concerns raised over the falsifying of family histories

The BBC has reported that geneticists in Manchester are concerned that women are claiming a false family history of breast cancer in order to get treatment (see BBC news story). Treatment can include the removal of their breasts. Such women may be suffering from a psychological disorder similar to Munchausen’s Syndrome by Proxy. People suffering for this syndrome may fabricate or induce illness in order to receive attention and treatment. The number of women fabricating their family history in this way is small, an estimated 1% of patients. However, as the genetic basis of other diseases is discovered, one might ask whether this phenomenon will increase.

Worryingly, geneticists are unable to verify the family history claimed by patients because of restrictions imposed by the Data Protection Act 1998 regarding consent. If a patient will not consent to allowing a doctor to access the appropriate medical records, their family history cannot be confirmed. Patients may then undergo unnecessary surgery and family members might be led to believe they have an increased risk of cancer themselves. As Professor Gareth Evans, consultant in medical genetics at St Mary’s Hospital, Manchester, told the BBC, ‘What we are concerned about are people who actually are fabricating it, know they’re fabricating it, and they’re the last people who are actually going to sign a consent form that’s going to let you find out that they haven’t actually had what they say they’ve had.’

 

Proposed changes to legislation on EU funding for stem cell research

A new resolution that impacts on the current terms of European Union funding for stem cell research was adopted last month by the European Parliament.

The main focus of the resolution is the trade in human egg cells, but it also includes a statement on the funding of embryo and embryonic stem cell research. Currently, the Parliament and the European Commission accepts the funding of research involving embryonic stem cells, but has specifically prohibited the EU’s research budget being used to create new human embryos for this work. The new resolution states that embryonic stem cell research carried out in member states where it is legal should be funded through the national budgets of these countries, and not by the EU. Furthermore, it proposes that EU funding should concentrate on alternative forms of stem cell research, using adult and umbilical cord cells. According to the three MEPs who promoted the new resolution, the European Parliament’s change of position was sparked by EU enlargement, with the inclusion of countries such as Poland, and concerns over the trade in human egg cells. The Human Fertilisation and Embryology Authority approved the use in the UK of eggs donated by woman in Romania, but some doubt has been cast over the methods by which these eggs were obtained.

Although the new resolution has been adopted by the Parliament, the EU Commission has yet to change its position, and the effect of these changes on the 7th Research Framework Programme of scientific funding remains unclear. - 15/4/05 Dr Ireena Dutta

 

GTAC publishes eleventh annual report

The Department of Health (DH) has announced that the Gene Therapy Advisory Committee (GTAC) has published their eleventh annual report at their annual public meeting in Manchester. The report gives details on the eleven gene therapy trials GTAC has approved in 2004, together with summaries of completed gene therapy trials and an analysis of 96 trials that have been carried out in the UK. The new trials focus on cancer, HIV and coronary heart disease. Over 70% of all applications to GTAC are for trials focusing on cancer, including colorectal cancer, prostate cancer, leukaemia and breast cancer. The DH is proud of its leading position in Europe in this field. The Health Minister, Lord Warner, stated in the press release that, “The government is committed to ensuring that the UK remains at the forefront of innovative medical research and has provided the funding towards new gene therapy clinical trials for inherited diseases such as Duchenne Muscular Dystrophy, cystic fibrosis and childhood blindness.” GTAC is likely to consider these new trials in 2005 or 2006.

The first gene therapy trial was approved in 1993. Gene therapy is described by the DH as involving, “…the deliberate introduction of genetic material into human cells for therapeutic, preventative or diagnostic purposes.” While progress has been slow, Prof Norman Nevin, Chairman of GTAC, notes in their report that some trials have shown promise, such as immunotherapy in cancer treatment. “My view is that we are beginning to learn more and more about the circumstances in which gene therapy may ultimately provide an alternative treatment strategy.” GTAC acts as the UK national ethics committee for gene therapy trials; no trial can go forward until it has been approved by GTAC as meeting the ethical criteria for research involving human subjects. GTAC also advises the government on developments in gene therapy research. 11/4/05 Dr Susan Wallace

 

NICE consultation on public health guidance

NICE (formerly the National Institute for Clinical Excellence) became the new National Institute for Health and Clinical Excellence on 1 April 2005, taking on the additional functions of the former Health Development Agency to create a single organisation responsible for providing national guidance on the promotion of good health and the prevention and treatment of ill health. This falls into three areas: public health, health technologies and clinical practice, under the control of the Centre for Public Health Excellence, the Centre for Health Technology Evaluation and the Centre for Clinical Practice, respectively.

NICE has launched a public consultation on the Centre for Public Health Excellence (CPHE) and how it will produce public health guidance. This is available from the NICE website until 10th June 2005. Broadly, guidance will relate either to specific public health interventions, or broader public health programmes, to prevent disease or improve health at population, community, organisational, group, family or individual levels. Genetics is not specifically mentioned in the consultation document, but it is stated that guidance produced by the CPHE will “recognise the wide spectrum of determinants of population and individual health”. – 11/4/05 Dr Philippa Brice

 

Cambridge epigenetics company reveals new partnership with the Babraham Institute

CellCentric, the Cambridge-based spin out company founded on the research of Professor Azim Surani, has announced the completion of an agreement with Babraham Institute that will give the firm exclusive rights to epigenetic-related intellectual property generated at the Institute. This agreement follows an investment of £250,000 in CellCentric by the Rainbow Seed Fund.

Professor Surani is based at the Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology in Cambridge. His work has focused on stem cells and the epigenetic factors that control how these cells develop and differentiate. Increasing knowledge in this area will provide insights into the mechanisms by which diseases such as cancer can occur, as well as assist in the production of potential new treatments. Epigenetic research is also vital to understanding how stem cells can be used to generate specialised cells types for use in regenerative medicine. Research work carried out at Babraham Institute has concentrated on cell communication and gene regulation, and their role in human disease.

CellCentric, which was founded last year, aims to use its epigenetic discovery platform to develop a variety of proprietary products for cancer based on proteins and small molecules. It will also fund research in the laboratory of Babraham scientist Dr Wolf Reik, to generate research reagents for biomanufacturing and disease modelling. The new investment from the Rainbow Seed Fund follows early stage funding for the company from a number of venture capital groups including the bioscience specialists Avlar BioVentures. The Rainbow Seed Fund was established by the Office of Science and Technology with £6million of capital, and invests in the commercialisation of work funded by a number of research councils and government bodies such as the BBSRC and Dstl. - 8/04/05 Dr Ireena Dutta

 

New Technology Programme competition announced by DTI

The Department of Trade and Industry have announced the launch of the second phase of awards from its Technology Programme. An open competition will decide the allocation of £100million of funding to support collaborative research and development. A number of key areas have been identified that UK industry can take advantage of, several of which have relevance to the life science sector. These include biopharmaceutical and bioprocessing, next generation lasers aimed at the manufacturing, healthcare and security industries and micro and nanotechnology. Calls for proposals are also sought in the fields of advanced materials, direct writing, emerging energy technologies, zero emission enterprise and validation of complex systems.

The Technology Programme forms part of the Government’s commitment to science and innovation and has a total budget of £320million over a three year period. The second phase of awards builds on the £145million that was made available last year. Promoting the importance of the awards, Lord Sainsbury, Minister for Science and Innovation, said, "Exploiting research can be a costly venture, even inhibiting for many businesses, but to keep Britain at the forefront of the global economy it is essential that we maintain inward investment in key innovative areas.”

The Technology Programme competition is open to industry and academia, including universities, other higher educational institutions, their spin-off companies and other research bodies, and further details of the application process can be found on the DTI website. – 4/04/05 Dr Ireena Dutta

Human Tissue Authority members announced

The Department of Health (DH) has announced the membership of the Human Tissue Authority (HTA). They are:

Baroness Hayman, Chair (announced 5 February 2005)
Prof Michael Banner, Director, ESRC Genomics Forum
Dr David Davies, Licensed anatomist, reader and lecturer in neuroscience
Mrs Shirley Harrison, Company Director
Prof James Ironside, Prof of Clinical Neuropathology, Univ of Edinburgh
Mrs Jane Jeffs, Retired Chief Officer of Community Health Councils (appointed by National Assembly of Wales)
Prof El-Nasir Lalani, Prof of Molecular and Cellular Pathology and Honorary Consultant Histopathologist
Ms Sharmila Nebhrajani, Chief Operating Officer and Finance Director, BBC New Media & Technology
Dr Andrew Reid, HM Coroner, Inner North London
Mr Keith Rigg, Consultant General & Transplant Surgeon, Nottingham City Hospital NHS Trust
Dr Katherine Robson-Brown, Archaeologist, Univ of Bristol
Ms Helen Shaw, Co-Director of INQUEST
Prof Sir James Underwood, Prof of Pathology, Univ of Sheffield and President, Royal College of Pathologists
Mrs Michaela Willis, Chief Executive Officer, National Bereavement Partnership

Two members are yet to be named, a member to be appointed by the Department of Health, Social Services and Public Safety, Northern Ireland, and a member with experience in nursing.

The HTA came into existence as of 1 April 2005, created as required by the Human Tissue Act 2004, which comes into force 1 April 2006. According to the DH, “The HTA will be the regulating authority for matters relating to activities such as anatomical and post-mortem examinations, transplantations and the storage of human material for education, training and research.” It will also act as the competent authority for the EU Tissue and Cells Directive, adopted in April 2004. The HTA will be responsible for writing Codes of Practice to implement the Act and the Directive, covering issues such as consent; definition of death; existing holdings; removal, storage and disposal of human tissue; and import and export of human tissue and organs.

The DH plans, in 2008, to combine the work of the HTA with that of the Human Fertilisation and Embryology Authority (HFEA) to create a new authority, the Regulatory Authority for Fertility and Tissue (RAFT), that will be responsible for the regulation and inspection of a wide range of uses of human tissue. However, RAFT’s proposed remit may change due to ongoing discussions. The House of Commons Science and Technology Committee’s recent report on Human Reproductive Technologies and the Law recommends that RAFT take on only the oversight of technical standards and quality management in regards to assisted reproduction. An expanded version of the Human Genetics Commission would be responsible for advising Government on relevant developments in treatments and research, a role currently held by the HFEA. The DH has announced they are conducting a review of the Human Fertilisation and Embryology Act 1990 with a public consultation exercise to be conducted in 2005. They will be considering the recommendations of the Select Committee as well as submissions from interested parties. Comments can be sent to review-hfe-act@dh.gsi.gov.uk. - 4/4/05 Dr Susan Wallace

 

Donor anonymity ends in the UK

The first of April marks the end of anonymity rights for people donating sperm and eggs. As reported by the BBC, children conceived through donations made after 31 March 2005 will have the right, at age 18, to have details about their genetic parent. That means the first requests cannot be made to the Human Fertilisation and Embryology Authority (HFEA) until 2023. Donations made prior to 1 April continue to fall under anonymity rules.

The rules for anonymity were changed when the Human Fertilisation and Embryology Authority (Disclosure of Donor Information) Regulations 2004 came into force in July 2004. The Regulations require that an applicant, such as an individual who was born through the use of donor eggs or sperm, can request detailed information about the donor from the HFEA, if that donation takes place after 31 March 2005. In addition to identity, the applicant can ask for the sex, height, weight, ethnic group, colour of skin, country of birth and marital status of the donor. The applicant can ask if the donor was adopted, the donor’s personal and family medical history, and what screening tests have been carried out on the donor. They can also ask about the donor’s children, the donor’s religion, and why the donor donated their eggs or sperm.

Concern has been raised as to whether the removal of anonymity for donors will inhibit people from donating. In a speech by Melanie Johnson, MP, she noted that there are many views on both sides of the issue (see PHGU newsletter January 2004). In some countries, while there may have been an initial drop in donors, the rates did improve with a shift to people who were more comfortable with the idea of being contacted. She also raised the question of whether it was right to withhold genetic information being held in a database from donor-conceived people, when those who are adopted are able to access information about their genetic parent. However, Dr Alan Pacey of the British Fertility Society, while citing the Society’s support of the removal of anonymity, cautioned in a press release last year that people might seek fertility services overseas if the donor rate does drop and donations become scarce. Education is needed to encourage donors; the National Gamete Donation Trust has been running a campaign, Give Life, Give Hope, to educate and encourage potential donors. - 2/4/05 Dr Susan Wallace

HGC/NSC Working Group reject DNA profiling of babies at birth

The Human Genetics Commission (HGC) and the UK National Screening Committee (NSC) have rejected a proposed national scheme to collect a DNA profile of every baby at birth, the BBC has reported. The Joint Working Group, formed by members from both organisations, concluded that while genetic profiling might provide clinical benefits in the future, at the moment the scientific evidence is limited. They recommend that the government revisit the issue in five years. The group had been tasked, as part of the Genetics White Paper, to consider the positive and negative aspects of the genetic profiling of babies at birth. Their report, Profiling the newborn: a prospective genetic technology?, has now been published.

Profiling was defined as, “…the analysis of a person’s entire genome in order to reveal the majority of the genetic variations.” The Working Group concluded that given the current state of scientific and medical knowledge that it was not practicable for this scheme to go forward at this time. The report states that, “…this is not likely to be affordable in the public health context in less than 20 years. It also raises a number of important ethical, legal and social issues which need to be addressed before any such scheme could be acceptable.” For example, there is a concern that information that came from the profile could be used in the future to discriminate against individuals in the areas of employment, insurance and education. The police might also use the information “…for unwarranted purposes.” If such a profile were to be collected from newborns, the information it contained would need to be adequately protected from misuse.

In the meantime, they believe that regulation might be needed in the commercial sector. Genetic profiling is feasible and companies are already offering it on an individual basis, raising issues such as the provision of genetic risk information to children. The Working Group does see the potential for genetic profiling to be of clinical use in the future but calls for further research into its implications. Research is also needed into genetic testing in children and into public attitudes on this issue. The results of such research would give reviewers a better understanding of the implications of genetic profiling when it is next considered. - 2/4/05 Dr Susan Wallace

Science Select Committee publishes report on human reproductive technologies

The House of Commons Science & Technology Select Committee has published its Report on Human Reproductive Technologies and the Law. The report, which controversially only represents the views of half the committee, advocates major changes to the current practice of regulating reproduction and embryo research. The report, in many of its recommendations, advocates a stepping back from regulation at a governmental level and giving more power to parents and doctors to make decisions, “…ensuring that reproductive decisions remain primarily in the private domain, governed by professional ethics and the law of consent.” The authors believe that this would provide a more flexible regulatory framework and benefit medical research. The report states that the Human Fertilisation and Embryology Authority (HFEA) has been overly cautious in licensing new research and this bureaucracy has hindered the advancement of medical research in general.

For example, the report recommends that the HFEA be abolished and replaced with the Regulatory Authority for Fertility and Tissue (RAFT). The Department of Health (DH) has already stated that the current work of the HFEA and the new Human Tissue Authority (HTA) will be combined in 2008. However, the report recommends that RAFT should have reduced functions from the HFEA. It would only be responsible for ensuring that laboratories meet technical and management standards. Parents would no longer need to go to a regulator to determine if they could have pre-implantation genetic diagnosis (PGD) to create a ‘saviour sibling’ to cure an ill child or if they were appropriate candidates for IVF under welfare of the child rules. They themselves would make those decisions with their doctor, with proper ethics oversight as required by the situation.

One specific recommendation that has been highlighted by the press is that parents should be allowed to choose the sex of their child when undergoing fertility treatment. The Select Committee believes that “The onus should be on those who oppose sex selection for social reasons using PGD to show harm from its use.” This position contradicts findings from a consultation held by the HFEA in 2003. The HFEA reported then that 80% of people in the UK did not want to use PGD for non-medical reasons such as sex selection. Likewise, a survey of 4,000 Americans, conducted in 2004, showed that while there was approval of PGD for helping save the life of a child, respondents did not believe it should be used for sex selection (see PHGU newsletter May 2004).

Other recommendations in the report include more research into the social impacts of assisted reproduction, that standards for providing in vitro fertilisation treatment should be improved, and that abortion issues be dealt with in a new Act which would be published in draft format and subject to pre-legislative scrutiny. Members of Parliament should be given a free vote on any legislation concerning assisted reproduction and embryo research and that a system of clinical ethics committees (committees that discuss ethics in clinical practice) be considered to act in parallel with research ethics committees. Also a single national commission should be created to develop policy issues in the areas of assisted reproduction, embryo research and human genetics. This commission would expand the remit of the Human Genetics Commission, which would disappear, and would include issues that the HFEA currently considers together with those that would fall under the HTA.

The views of the five dissenting Committee members, almost half the Committee membership, are presented in a Special Report and a press release. According to the release, the dissenting members believe that the report is “…flawed in adopting an extremely libertarian approach…” to the issues. “It was an unbalanced approach…which neither reflected the evidence received nor represented the views of a majority of the Committee.” They state that there had been moves to make the report more balanced through redrafting, however other commitments made it impossible for members to attend all of the Committee sessions. Limited time was given to discussion of amendments to the report, which they believe “…further distracted from the report.” It was agreed that a Special Report, recording the dissenting view, would be issued with the main report. However, the text, except for the opening sentence stating that there was a dissenting view, was subsequently removed from the Special Report. According to the press release, it is available in the proceedings of the Special Report itself. Because of the division amongst the members, it was decided that no press conference would be held.

It is unclear how this report will influence decision making on these issues. The terms of reference for the committee were to consider the future of the HFE Act and the HFEA. The Department of Health has announced plans to review the Human Fertilisation and E