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28 October 2005The European Parliament (EP), in their latest sitting, has agreed the text of a resolution on patenting biotechnological inventions. The resolution confirms Parliament’s rejection of research on human embryos and calls for the European Patent Office (EPO) and Members States to grant patents on human DNA only for a ‘concrete application’ and for the scope of the patent to be limited to that application. It also calls for the European Commission (EC) to file a notice of opposition to patent EP1257168, which covers a method for cryopreserving sperm cells that would enable the sex of the child to be chosen during the artificial insemination process. The EEP-ED Group within the European Parliament has dubbed this the ‘designer baby patent.’
In August the EC published their second report looking at Member States’ implementation of the Directive on the legal protection of biotechnological inventions (98/44/EC). The report noted that some States have granted patents on DNA sequences that cover the original disclosure in the patent application as well as possible future uses of the sequence. Other countries have taken a more conservative approach, only granting a patent for the specific application, while France has totally banned patenting of DNA sequence. The EP, in this resolution, has given its support to the more restricted ‘purpose-bound protection.’
The contentious patent was awarded to a US company, XY Inc., in November 2002. According to an EPO press release, some Members of the EP claim that the patent, entitled ‘Method of cryopreserving selected sperm cells,’ violates the Directive as it covers non-patentable human germ cells. The Directive states “Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality.” The EPP-ED Group believes that “…the spirit of the Directive opposes patents on embryonic stem cells.” The European Patent Convention, which incoporates relevant portions of the Directive into European patent law, confirms that the human body and its elements cannot be patentable inventions. But “…an element isolated from the human body or otherwise produced by means of a technical process may constitute a patentable invention, even if the structure of that element is identical to a natural element.” The EPO, while acknowledging the right of anyone to oppose a patent, “…emphasises that it follows an extremely cautious approach in patenting biotechnological inventions.” The EPO had agreed in June 2005 to stop making decisions on patent applications involving human embryonic stem cell technologies [Schubert, S. Nature (2005) 435:720-1].
The EP will contest the grant of the patent by initiating an opposition procedure. The EPO’s Technical Board of Appeal is expected to make a first decision on the subject on 18 November. However, this Board is able to refer the issue to the Enlarged Board of Appeal, the EPO’s highest instance, for a definitive legal ruling.
20 October 2005A new international collaboration in stem cell banking has been established in Seoul, South Korea this week. The initiative forms part of the new World Stem Cell Hub, which has been launched by the South Korean government. The Hub will be lead by Professor Woo Suk Hwang, whose group have been responsible for deriving the first embryonic stem cell lines by therapeutic cloning. The group also recently announced the production of the first patient specific stem cell lines (see previous news item in PHGU newsletter).
The Hub will be based at the Seoul National University Hospital but there are plans for other centres based around the globe. These will provide training for researchers as well as a bank of cell lines and, where it is permitted, assist in the creation of new patient-specific embryonic stem cell lines. The first branches of the Hub are due to be established in the UK and California, with the possibility of further centres in other parts of Europe such as Sweden and Spain. However, although South Korea will create a foundation to fund the Hub’s headquarters and to support Korean scientists travelling abroad, the other international centres will be expected to source their own funding.
It is hoped that the new international stem cell bank and the wider Hub initiative will facilitate global cooperation in stem cell research by assisting in the production of stem cell lines with a range of defects that cause diseases such as diabetes. These lines could then be distributed and used by researchers across the globe. Commenting on the plan, in an interview with Associated Press, Professor Hwang said, “When the use of these stem cells is limited to a particular country, it takes much too long to create technologies usable for the whole of humanity. By creating a global network, we plan to share stem cells created in each country and share information on those stem cells." The Hub has also received support in the UK from the Medical Research Council. As reported by the BBC, Professor Christopher Higgins, director of the MRC Clinical Sciences Centre, said: "It is a very positive step forward. If we are going to make use of embryonic stem cells for therapeutic purposes it is very important that there is access for all the researchers who need them."
The world’s first stem cell bank was established in the UK in 2004 and currently holds over thirty adult and embryonic stem cell lines.
17 October 2005Researchers have reported in Science that nearly 20% of all protein-coding human genes have been patented, with the majority patented by private biotechnology companies [Jensen K. and Murray F. (2005) Science 310, 239-240]. This accounts for 4382 of the 23,688 genes published in the US National Center for Biotechnology Information’s database. The authors investigated United States patents, but it is likely that the same genes will have been patented in Europe, according to a Guardian newspaper report [Ravilious, K, Guardian 14 October 2005].
The genes are claimed in 4270 patents that are owned by 1156 different assignees. Approximately 63% of the assignees are private firms. One firm, Incyte Pharmaceuticals/Incyte Genomics, has patents on 2,000 human genes. A majority of the patented genes, at least 3000, have only a single intellectual property (IP) rights holder. But some genes related to human health and disease, such as BRCA1 that is linked to early onset breast cancer, have multiple patents covering rights to various uses of the gene. Researchers who want to work on a multi-patented gene may have to spend large amounts on complex licensing agreements in order to gain access.
The authors note that “…the classic argument in support of gene patenting is that strong IP protection provides incentives crucial to downstream investment and the disclosure of inventions.” On the other hand, critics of gene sequence patents fear that broad patents will hinder downstream research activities. Also, innovators may be deterred by an ‘anticommons’ effect, where “…people underuse scarce resources because too many owners can block each other” [Heller M. and Eisenberg R. (1998) Science 280, 698-701]. Little empirical research has been done on the extent of gene patenting, according to Jensen and Murray. They suggest that the current patent examination system could be reviewed to see if the process is responsible for multiple conflicting patents being granted on the same gene. Genes that have multiple patents provide an opportunity “…to explore the variety of arrangements used to facilitate or block access to gene-based research and the impact of these arrangements on future innovators.” Such studies could provide beneficial information to inform the patent debate.
14 October 2005Seventy-three Members of the European Parliament (MEPs) have sent an open letter to Commission President Barroso asking the European Commission to not fund human embryonic stem cell (hESC) research under the Seventh Research Framework Programme (FP7). In the letter the MEPs state that Member States where hESC research is prohibited should not have to share the cost of funding research that is in conflict with their national law. Funding should be the responsibility of those countries that support such research. Instead, EU funding should be given to somatic (adult) stem cell and umbilical stem cell research projects, which are accepted by all Member States. The European People’s Party and European Democrats (EPP-ED) Group in the Parliament, the largest political group within the Parliament, state in a press release that they initiated and garnered support for the letter.
The letter confirmed the European Parliament’s support for a resolution passed on 10 March 2005 on the trade in human egg cells that included a call for the EU to refuse to fund hESC research. The resolution stressed Parliament’s concern that women in developing countries could be enticed by financial incentives to donate their eggs, with such practices resulting in their exploitation. The resolution specifically cited a clinic in Romania that specialised in donating eggs to EU nationals, particularly UK citizens. The resolution also noted that the UK had considered a £1000 payment to women donating their eggs. The Human Fertilisation and Embryology Authority, in their Sperm, Egg and Embryo Donation (SEED) Report, has recommended a limit of £250 for loss of earnings incurred. The resolution also asked the European Commission to refuse to fund embryo and hESC research; the open letter to Commissioner Barroso links these issues together, stating, “It is very clear that egg cells are needed for every embryo and that therefore there is a risk that women become instrumentalized as ‘suppliers of raw material.’”
Perhaps ironically, the UK, during their presidency of the Council of the EU (July-December 2005), will be responsible for redrafting the FP7 proposal, based on discussions held by the Competitiveness Council. UK Minister for Science and Innovation Lord David Sainsbury has said that the specific issues to be addressed will be research ethics including hESC research and the proposed European Research Council (ERC). Discussions on the next draft of FP7 will be held at the next meeting of the Competitiveness Council on 28-29 November 2005.
11 October 2005Japanese companies have announced that they have built desktop DNA machines that will allow doctors to analyse patients’ DNA as a prelude to prescribing [see D. Cyranoksi, Nature 437:796; BioNews 329]. Doctors will be able to analyse a single drop of a patient’s blood and, in one hour, according to claims, be able prescribe that patient the drug and dosage most appropriate for them. The machines will be tested first on patients who are being prescribed one of two drugs: an antibody called irinotecan and the anticoagulant warfarin. For some patients with mutations in their mitochondrial DNA, taking irinotecan can cause hearing loss. Likewise, some patients suffer from excessive bleeding when taking warfarin. These complications make these two drugs logical targets for personal testing prior to prescribing. The DNA analysis would tell doctors if a patient will react adversely to these drugs or whether they will be able to benefit from them.
Sir David Weatherall, who recently chaired a committee reporting on personalised medicine on behalf of the Royal Society, sounded a cautionary note. As reported by Nature, he said in the case of warfarin, “…metabolism…is related to at least two genes whose interaction is not understood. Other factors, such as the patient’s age or additional drugs being taken, also need to be considered.” The Royal Society report stated that these and other variables that affect a patient’s response to a drug (e.g. dosage, inherited factors, adherence to the drug regime, environmental factors) interact in complex ways and that more research is needed. Their report concluded that personalised medicine is still many decades from becoming a reality in mainstream clinical practice. Takaaki Sato, of the scientific equipment maker Shimadzu, disagrees. He believes that products such as theirs will be in use for day-to-day diagnosis and treatment in the near future. Initially, though, he agrees that their machine will be most useful for research purposes.
7 October 2005The Human Fertilisation and Embryology Authority (HFEA) has published its report from the Sperm, Egg and Embryo Donation (SEED) Review. Begun in November 2004, the SEED Review sought views from the public and stakeholders on a variety of issues related to the donation of gametes and embryos for fertility treatment and research. Results from the Review will help the HFEA decide whether to revise or maintain existing policies surrounding donor-assisted conception. In addition, the Review will enable the HFEA to consider what revisions will be needed to adequately transpose the European Directive on Tissues and Cells into UK law. The Directive imposes new standards for quality and safety that UK fertility clinics will have to meet. These requirements, with some exceptions, become mandatory in April 2006.
The SEED Review makes several recommendations including:
The Review also makes recommendations regarding compensation for donors (see BBC news report 7/10/05). Donors will continue to be reimbursed for any reasonable out-of-pocket expenses incurred in relation to donating. In addition, donors may receive compensation for loss of earnings up to a limit of £250, with the daily maximum set at £55.19, the same for those serving on juries. The previous amount of £15, plus reasonable expenses, for a donation was seen as too little. However, giving too high an amount of compensation might inappropriately encourage donors. The HFEA notes “…that additional payment might encourage donors to disregard risks to the health or to withhold important medical information, or that it might attract donors with whose motives, when disclosed, could be difficult for offspring to come to terms.” The EU Tissue and Cells Directive states that donations must be voluntary and not seen as a way to make a profit. The limit of £250 is seen by the HFEA as just compensation for loss of income but not attractive enough to cause people to donate for other than altruistic motives.
The HFEA has also reported on the make-up of UK donors. Sperm donors during 2004-2005 were primarily over the age of 30, with approximately 40% already having children of their own. Ten years ago the majority of sperm donors were aged between 18-24. The age distribution of egg donors has not changed significantly during the same time period. Angela McNab, Chief Executive of the HFEA, said, "Understanding who donors are is a significant part of understanding how the area of donor-assisted conception works and how it can be made better...."
3 October 2005Preimplantation genetic diagnosis (PGD) is a technique whereby embryos created by in vitro fertilisation are screened for the presence of a disease associated genetic variant, and only embryos without the variant are implanted in the mother. The Human Fertilisation and Embryology Authority (HFEA) has announced that it will hold a public discussion on the use of preimplantation genetic diagnosis (PGD) for lower penetrance conditions – that is, conditions for which possession of a disease associated genetic variant does not necessarily mean that the disease will develop. For example, the penetrance of Huntingdon’s Disease is virtually 100%; whereas for the breast and ovarian cancer associated gene BRCA1 variants, penetrance is 50-80%, such that up to 50% of individuals with the gene variant will not go on to develop breast or ovarian cancer.The HFEA has already licensed the screening of embryos for a form of hereditary colorectal cancer, Familial Adenomatous Polyposis (FAP), which is not completely penetrant, but in this instance penetrance is both greater than 90% and is also typically early onset, with disease developing in young adults. In contrast, the lower penetrance conditions tend to affect people in later life (ages 40-80). The HFEA wishes to hear the views of stakeholder groups and the wider public on the possibility of licensing centres to screen embryos for lower penetrance conditions in the future. It will release a discussion document on the topic in October, and a public meeting is to be held in December of this year.
4 October 2005Recent draft guidance on the design of clinical trials involving gene transfer technology issued by the US Food and Drugs Agency (FDA) has called for long-term follow-up of trial participants, in order to properly monitor for long-term adverse effects of gene therapy treatments and mitigate their potential impact on participants. Gene transfer technology is defined as gene therapy products or cells or tissue that has been transduced with gene therapy products ex vivo. The document also provides a framework for risk-assessment to determine whether the trial involves high risks that merit long-term follow-up. Factors considered likely to increase the risk of delayed adverse events include persistence of the viral vector, integration of genetic material into the host genome, prolonged expression of the transgene, and altered expression of the host’s genes.
Special recommendations are made for trials involving the use of retroviral vectors, due to the occurrence in 2003 of therapy-associated leukaemia in three out of eleven children who received gene therapy for the rare genetic condition X-linked Severe Combined Immunodeficiency (X‑SCID) in a French trial. The leukaemia was caused by insertion of the retroviral vector used for the gene therapy. As well as increased levels of post-trial surveillance, it is recommended that consent forms for such trials include information about the risks of malignancies, including reference to the X-SCID trial.
28 October 2005An article in Nature has announced the release of the first phase of the human haplotype map data. The International HapMap Consortium which consists of over 200 scientists from the US, UK, Canada, China, Japan and Nigeria are also presenting the results of the project at the American Society of Human Genetics conference, currently underway in Salt Lake City. This project results in a map of the common differences in the human genome and is a natural extension of the Human Genome Project.
Once the human genome sequence was finished, the logical follow-on project was to look for the indicators or markers that signify the differences between individuals, and their susceptibility to various diseases. Humans are genetically 99.9% identical to each other and the remaining 0.1% consists of the variation that accounts for important differences between individuals. There are thought to be around 10 million single nucleotide polymorphisms or SNPs in the human genome. In this project, over 1 million SNPs were genotyped in 269 individuals representing populations from Africa, the Far East and Western Europe, with 300,000 of these being ‘tagSNPs’. By using these tagging SNPs researchers were able to capture 90% of the information that would have been obtained by looking at all 10 million SNPs, since these are not all inherited independently. All the SNPs used in the tagSNP project were called common SNPs, because they all had a minor allele frequency of at least 5% and were spaced at approximately 1 every 5,000 bases. In addition to the 300,000 tagSNPs, the scientists also looked at ten 500 kilobase regions (the ENCODE regions) in detail and typed all SNPs identified in these regions irrespective of allele frequency in the full 269 samples, with an average spacing across the ten regions of 1 SNP typed every 279 bases. Data generated during the project were consequently analysed to look at the relationship or linkage disequilibrium (LD) between SNPs and across regions. The projected Phase II of the HapMap project aims to type an additional 4.6 million SNPs in the 269 samples and further SNPs and samples across the ENCODE regions.
The project is of considerable benefit to the scientific community, as the data produced during this project is publicly available and is already being utilised by other research groups. Additionally, the public SNP database, dbSNP, now contains 9.2 million reported SNPs; an increase of 6.6 million SNPs as a result of this venture. Scientists can now use bioinformatic tools to prioritise the SNPs thought to be putatively functional in order to narrow down the search for the causal variant of their particular disease of interest. However, other leading scientists have issued a note of caution, citing the fact that the project doesn’t look at rare variations (those with a minor allele frequency of less than 5%) that may be important in complex diseases. Another potential drawback may be that the data in the reported populations may not match well with that of a study population, therefore limiting its utility. Nonetheless it is agreed that the work published by the International HapMap Consortium does represent a considerable resource for other scientists, both in terms of information content and in terms of time and effort saving.
Comment: The immediate relevance of the publication of this work to human health is as yet unclear. There is no doubt that the report represents an advance in the ultimate goal of understanding human disease and facilitating personalised medicine, yet the direct benefits of this study are harder to perceive. If the genetic determinants of a complex disease are common, then this data may greatly advance the study of the disease, yet if the determinants are rarer, then Phase II of the HapMap project may be of greater utility than the current data release. The long term aim must be to understand the effect of these genome variations on public health.
26 October 2005
Embryonic stem cell lines are usually derived from the inner cell mass of the blastocyst, an early developmental stage of the mammalian embryo. This process leads to the destruction of the embryo and in the case of human embryonic stem (ES) cell research has led to a number of ethical objections from groups opposed to this elimination of a potential life.
Two novel methods for the production of embryonic stem cell lines, that avoid the destruction of viable embryos, have recently been proposed. The first method, reported in an advance online publication in Nature by Meissner and Jaenisch, uses a protocol termed 'altered nuclear transfer' (ANT) to create blastocysts which are incapable of developing into viable embryos but can still be used for the derivation of embryonic stem cell lines. During normal embryonic development, survival of the blastocyst after implantation in the uterus is dependent on the formation of the trophectodermic cell lineage. This lineage gives rise to the cells that form the foetal-maternal interface within the placenta and thus is essential for the development of the embryo. The inner cell mass (ICM) is the second cell lineage that is formed. It is responsible for all subsequent lineages in the embryo and when cultured in vitro gives rise to embryonic stem cell lines. The ANT method is based on the prevention of trophectoderm, and therefore placental, development in a process that leaves the ICM unaffected. The blastocysts that are created using this process have no potential to develop beyond this stage into a viable organism, but can still be used to derive embryonic stem cell lines.
The ANT method relies on genetically altering a somatic donor cell to prevent trophectoderm development, before transfer of its nucleus into a recipient denucleated or 'empty' egg cell. In this study the authors knocked-down expression of the Cdx2 gene in mice, in order to determine the effectiveness of the ANT approach. Cdx2 encodes a trophectoderm-specific transcription factor that is essential for the establishment and function of the trophectoderm lineage. Previous studies have shown that Cdx2-deficient blastocyts fail to maintain a blastocoel and lack epithelial integrity but do form an ICM and generate ES cells in culture. The authors used RNA interference (RNAi) to knock-down expression of the gene by introducing short hairpin (sh) RNAs against Cdx2 via a viral vector. This vector was used to infect mouse fibroblasts and expression of green fluorescent protein (GFP) was used as a marker to select cells to be used as donors for nuclear transfer. The researchers created a total of 526 new cells by nuclear transfer and of these 61 developed to the blastocyst stage. The Cdx2-deficient blastocysts were found to be morphologically abnormal and did not express Cdx2 when assessed by both immunohistochemistry and RT-PCR. None of the Cdx2-deficient blastocysts were able to implant and develop when transferred to the uteri of pseudo-pregnant mice, compared to 40% of a control sample.
The researchers then went on to assess whether ES cell lines could be derived from the Cdx2-deficient blastocysts. Following expansion in cultures ICMs taken from these cells generated ES cell lines with an efficiency that was comparable to that of nuclear transfer blastocysts derived from wild-type fibroblasts. The pluripotency of these lines was assessed by testing their ability to form chimeras when injected into diploid blastocysts. The GFP-labelled cells contributed to most tissues with the exception of the intestine, reinforcing previous reports that Cdx2 is necessary for development of the gastro-intestinal tract. In order to determine if full pluripotency could be restored to these cell lines, a plasmid was introduced which deleted the Cdx2 shRNA and thus restored normal Cdx2 expression and function. Nuclei from this new line were then transferred to recipient oocytes, and blastocysts which expressed wild-type levels of Cdx2 were generated. ES cell lines derived from these blastocysts were able to produce all somatic tissues, including intestinal cells, and these blastocysts were also able to implant when placed in pseudo-pregnant female mice. The researchers were thus able to generate abnormal blastocysts that were intrinsically unable to implant in the uterus and develop into a foetus, but which could be used for the derivation of ES cell lines which displayed reduced development potential compared to wild-type ES cells. However, full pluripotency could be restored by reversing the knock-down of Cdx2 expression.</