News

18 November 2005After a period of consultation, the European Commission has published its draft regulation on advanced therapy medicinal products and related explanatory documents. The Commission proposal will now go to the European Parliament and Council for co-decision. Human tissue engineering, gene therapies and cell-based therapies will fall under the finalised regulation. While gene and somatic-cell therapies are currently subject to Community legislation, human tissue-engineering has lain outside the regulatory framework. This has resulted in divergent national standards that have negatively affected efforts to innovate and compete in this potentially lucrative market. The regulation’s purpose is to harmonise standards across the EU in all these areas of biotechnology, to enable easier access to therapeutic products for patients as well as to increase Europe’s international competitiveness in these fields.

The draft regulation contains “…rules to facilitate…” the production of therapies, according to a Commission press release. The main points of the proposal are:

• The requirement for a centralised marketing authorisation procedure
• The creation of a new, multidisciplinary expert committee, the Committee for Advanced Therapies, within the European Medicines Agency (EMEA), to provide scientific advice on data related to advanced therapy medicinal products
• The provision of technical requirements specific to these products to ensure quality, safety and efficacy
• Risk management and traceability requirements
• Scientific advice provided by EMEA
• Incentives for small and medium-sized enterprises

European regulations must be adopted directly in national legislation; unlike directives there is not an opportunity to transpose regulations in light of existing national law. In recognition of the differing Member States’ laws governing the use of embryonic stem cells in research and therapeutics, the regulation does not impose rules regarding their use. It devolves this decision, leaving it to the Member States to decide. The regulation does observe the principles reflected in the EU Charter on Fundamental Rights, noting “…that human tissue- and cell- based products should be founded on the philosophy of voluntary and unpaid donation, anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient.” 

Commission Vice President Günter Verheugen has stated, regarding the draft regulation, “Advanced therapies have a huge potential, both for patients and industry. With this proposal we guarantee the highest level of health protection for patients. At the same time we give the biotech industry a coherent EU-wide framework which allows them to innovate, grow and create jobs.”

24 November 2005The internationally renowned stem cell researcher Professor Hwang Woo-Suk has been forced to resign from all the official positions he held in South Korea. Professor Hwang had been a leading force in embryonic stem cell research, pioneering new discoveries such as the creation of the first cloned human embryos and the first patient specific stem cell lines.

Some ethical doubts about the research practices within the Hwang group had first been raised in 2004, when Nature magazine published a claim that work had been conducted using egg cells that had been donated by a junior researcher. The process of egg donation is an invasive one, which also requires a series of hormone injections. Many ethical concerns surround donation by research group members, due to the possibility that junior members may be coerced or pressurised into the process by senior researchers. Although this claim had been consistently refuted by Professor Hwang, the issue arose again earlier this month when a close collaborator from Pittsburgh University, Professor Gerald Schatten, terminated their joint work, citing “concerns regarding oocyte donations”. Professor Schatten had been a co-author with Hwang of two key stem cell papers, namely the derivation of the first patient-specific stem cell lines and the creation of Snuppy, the first cloned dog.

Professor Hwang today admitted in a press conference in Korea that in fact two members of his research group had donated their own oocytes for research purposes. Although he stated that he had been unaware of their actions, he had not disclosed them when they did come to light and had continued to issue denials. “I again sincerely apologise for having stirred concern at home and abroad," he is quoted as saying during the press conference,"Being too focused on scientific development, I may not have seen all the ethical issues related to my research.” It also emerged that the Hwang lab had also used egg cells in their research that had been obtained in exchange for payment. As reported in Nature magazine, a collaborator from ," he is quoted as saying during the press conference,".” It also emerged that the Hwang lab had also used egg cells in their research that had been obtained in exchange for payment. As reported in , a collaborator from MizMedi Hospital in Seoul has admitted that twenty eggs he was responsible for procuring were paid for, although Professor Hwang was unaware of this. At the time the payments were made this was not offence in Korea, as legislation to prohibit this practice has only recently been introduced.

Although Professor Hwang has stepped down from all his public appointments, including the chairmanship of the World Stem Cell Hub, he will continue to lead his research group at Seoul National University. The controversy surrounding his work demonstrates that the ethical debate surrounding embryonic stem cell research is not just limited to the creation and destruction of embryos but also stretches much wider to include issues surrounding the regulation of gamete donation and the circumstances under which this occurs.

The Office of Genomics and Disease Prevention, part of the US Centers for Disease Control and Prevention (CDC), has released a new report, Genomics and Population Health 2005. This follows a previous report in 2003, and is intended to be of value for “advancing the integration of genomics into public health research, policy, and practice” (see Director’s message).

The Genomics and Population Health 2005 comprises three main sections:

1. Public health research

2. Genetic testing

3. Public health practice

Within these sections, the document includes reports from a 2004 workshop, Incorporating Human Genomics into Acute Public Health Investigations; the CDC Family History Public Health Initiative, and the Evaluation of Genomic Applications in Practice and Prevention project. Updates on the work of the Centers for Genomics and Public Health and programmes to develop capacity for the integration of genomics into chronic disease prevention are included, along with chapters on genomics and vaccine safety; direct-to-consumer marketing of genetic tests for breast cancer susceptibility; ACCE reviews of genetic tests for the BRCA1/2 (breast cancer) and CFTR (cystic fibrosis) gene mutations; newborn screening for cystic fibrosis and enhancing genetic testing for rare diseases.

7 November 2005The Public Population Project in Genomics (P3G) is an international consortium of public bodies involved in major genetic epidemiology projects and biobanks. It was created to develop and manage a multidisciplinary infrastructure for comparing and combining results from large-scale population genomic studies, to facilitate the translation of research into clinical benefits in terms of disease prevention and treatment.

The P3G Observatory, launched last month, is the knowledge transfer platform of the P3G project. It aims to disseminate scientific and technical information produced by member groups, and to provide suitable tools for the development, co-ordination and comparison of studies. To this latter end, the Observatory contains a catalogue of all major population genomics studies around the world (including those run by groups who are not P3G members) that can be used to access and compare information about different projects. There are fifteen such studies listed at present.

3 November 2005An anonymous sperm donor has been traced by his 15-year old genetic son, using an internet based genealogy DNA-testing service. The boy supplied his own cheek swab sample to FamilyTreeDNA.com, which identified two men with genetically similar Y-chromosomes, both sharing the same surname. Although the sperm donor himself had never supplied DNA to the database, this surname information combined with the details the boy already knew – his genetic father’s date and place of birth – was sufficient for the boy to identify the donor. He used another online service, Omnitrace.com, to find names of everyone with the same date and place of birth, and of these only one had the surname identified via the DNA database. The boy reportedly made contact with this man within ten days (see BBC news report).

New Scientist magazine commented that the success of the boy’s search ”has huge implications for the hundreds of thousands of people who were conceived using donor sperm. With the explosion of information about genetic inheritance, any man who has donated sperm could potentially be found by his biological offspring”. In the UK donor anonymity was lifted in April of this year, so that information that can identify a sperm, egg or embryo donor can be given to offspring once thy reach the age of 18, but an estimated 25,000 individuals have been born from donated sperm alone in the last 15 years. In other countries such as the US, sperm donation continues to be anonymous in many cases.

Lindsey Marshall of UK DonorLink, which brings together consenting donors with adult offspring conceived using donated sperm or eggs, commented that there were serious ethical issues surrounding the case, especially for anonymous donors who have subsequently had families of their own who may be unaware that they had been a donor, saying: "The ramifications are huge. People's lives can be turned upside down". It is also significant that donors who are independently traced by their offspring have not consented to contact with them, and neither parties receive any counselling or support as they would via an organisation such as UK DonorLink.

Bryan Sykes, a geneticist from the University of Oxford and chairman of another genetic genealogy service, OxfordAncestors.com, commented that not only did the case raise “serious questions about whether past promises of anonymity can be honoured” but that the potential implications were even wider, citing the example of similar approaches being used forensically to trace criminals (see New Scientist article).

3 November 2005Researchers at the University of Sheffield School of Health and Related Research and the Genetic Interest Group have released a report of a project investigating the doctor-patient relationship. “‘Expert patients and non-expert doctors’: the challenges and opportunities of role reversal in the doctor-patient relationship” examines the changing nature of this dynamic. Traditionally the doctor has held the expert role in the consultation process. However, with the rise of information easily available via the Internet and patient support groups, patients and parents of sick children may often have (or believe they have) more and better knowledge of specific conditions than their general practitioner.

In this qualitative study, researchers interviewed GPs, patients and parents of children with acute conditions “…to identify elements which enhanced, and elements that hindered, the doctor-patient relationship when the patient’s knowledge of their condition exceeds that of their doctor.” They concluded that this role reversal could be both beneficial and detrimental to the relationship. For example, problems arose when patients/parents lacked the confidence to negotiate with the doctor over treatment decisions, as this “…might appear to call into question the doctor’s competence.” GPs can be made to feel uncomfortable when patients/parents have more knowledge than they do. Conversely, when both parties respected each other’s level of competence, the patient/parent’s knowledge aided the decision-making process. When there was a lack of mutual respect, the relationship suffered.

The report concludes with recommendations for enhancing the doctor-patient relationship in this age of the “informed patient.” The authors note some of the consequences of an unequal relationship. “Trivialisation of a condition by their doctor was demoralising of patients/parents” while “Patients who misuse their GP can detract form the service for all users…” As patients continue to learn more about their health situation, respect by both parties of the expertise and limitations of each will only improve the consultation process.

28 November 2005Genetic diversity in melanoma. Meltzer PS (2005) N. Engl. J. Med. 353, 2104-2107. Perspectives article accompanying a report of molecular DNA profiling of melanoma samples.

The X-inactivation yo-yo. Reik W and Ferguson-Smith AC (2005) Nature 438, 297-298. News and views piece on the mechanisms underlying the selective inactivation of X-chromosomes and its role in imprinting.

Nature Reviews RNAi collection. A selection of recently published Reviews, Perspectives and Highlights on RNA interference, now available from: http://www.nature.com/focus/rnai/index.html

21 November 2005Health information altruists – a potentially critical resource. Kohane IS and Altman RB (2005) N. Engl. J. Med. 353, 2074 – 2077. ‘Sounding board’ piece about how human genetic information can be used to improve health, and how concerns about privacy and protection of genotypic and phenotypic data may limit the benefits from large-scale genomic health projects and databases.

Metabolic disorders in the center of genetic medicine. Levy HL (2005) N. Engl. J. Med. 353, 1968-1970. Editorial on the close involvement of inherited metabolic diseases with the study of genetic influences on health, and accompanying a report of a novel metabolic disorder involving inadequate levels of glutamine. The articles notes that current newborn screening for metabolic disorders is primarily based on identifying abnormally high levels of metabolites, and questions whether it should also look for abnormally low levels.

All in the mind of a mouse. Dennis C (2005) Nature 438, 151-152. News feature on the use of genetically engineered mice as models for genetic aspects of psychiatric diseases.

Patients at risk of colorectal cancer. Kielne P (2005) BMJ 331, 1033-1034. Editorial accompanying report on prevention of colorectal cancer by colonoscopic surveillance of individuals with a family history of the disease – in particular, those with only moderate disease risk, based on their family history.

Is public health coercive health? Cottam R (2005) Lancet 366 1592-1594. Commentary addressing the question of whether government interventions intended to improve public health constitute a ‘Nanny State’, and whether or not this is a bad thing.

A case report in the Lancet outlines an unusual situation of posthumous diagnosis. The younger child of a family developed a severe disease involving progressive neurological decline, and died at the age of seven. No diagnosis was made during the child’s lifetime, despite extensive clinical investigation, although an occupational therapist had mentioned the possibility of Rett Syndrome. More than ten years after the child’s death, the mother read an article on this condition and became interested in discovering whether or not her daughter had indeed suffered from it, especially since her older child was approaching reproductive age and the family was concerned for the health of potential grandchildren.

Fourteen years after her death, DNA was extracted from a baby tooth from the deceased child; sequencing revealed the presence of a mutation that is known to cause Rett Syndrome. The benefits of this diagnosis to the family were significant. Not only did it allow reassurance that their son was not a carrier of the mutation and that any grandchildren would not be at risk of the disease that had affected their daughter, but it also brought additional psychological benefits in terms of alleviation of guilt; in the absence of a diagnosis, the parents had hitherto blamed themselves for their daughter’s condition based on a fall and a vaccination received around the time her symptoms became apparent [Leonard H et al. (2005) Lancet 366, 1584].

Comment: This report is of interest both as an example of the increasing power and scope of DNA testing technologies to identify disease-associated mutations and as a demonstration of the benefits of diagnosis even in cases where the affected family member is deceased. Of course, this posthumous diagnosis, of such value to the family of the child in question, would not have been possible without the existence of a body part (retained in this instance by the parents themselves) from which to obtain a DNA sample. This provides an interesting perspective on the potential future medical benefits from retained tissues, which could not necessarily be anticipated during the lifetime of an individual, or at the time of his or her death.

The removal and storage of some form of DNA sample from individuals affected by a condition for which no diagnosis has been made (whether during life or on their decease) might be a wise move, for potential diagnostic testing in the future when new information or technology might permit a posthumous diagnosis. However, whether storage for an unspecified purpose (even with appropriate consent) would be legally permissible under the terms of the Human Tissue Act is not clear, since it could not be certain that the sample would be of use for ‘determining the cause of death’ or ‘obtaining scientific or medical information about a living or deceased person which may be relevant to any other person (including a future person)’.

8 November 2005A population-based study published in the BMJ last month reports on the recurrence of pre-eclampsia across generations. Pre-eclampsia, or PE, is a common and serious hypertensive complication of pregnancy, which can cause significant mortality and morbidity for both mothers and babies; risk of the condition is influenced by family history. However, the genetic factors involved are complex. It has been recognised for many years that maternal susceptibility to the condition may be inherited, but more recently it has been discovered that fetal genes (inherited from either the mother or father) can also influence risk.

The authors of the new study set out to examine these two different pathways of familial risk transmission (via maternal and fetal susceptibility) by looking at birth data from a Norwegian population based birth registry, between the years 1967-2003 [Skjærven R et al. (2005) BMJ 331, 877-879]. They examined whether women and men born after a pregnancy complicated by PE had a higher risk of parenting a pre-eclamptic pregnancy themselves, compared with individuals born after a normal pregnancy.

Women born after a pre-eclamptic pregnancy were found to have an increased risk of more than two-fold (2.2) of themselves developing PE compared with other women. This level of risk was approximately the same for second pregnancies following a first pregnancy not affected by PE. Men born after a pre-eclamptic pregnancy were found to have an increased risk of 1.5-fold of themselves parenting an affected pregnancy. Sisters of these women and men, who were born following pregnancies not affected by PE, were nevertheless found to have a two-fold increased risk of parenting a pre-eclamptic pregnancy, but brothers did not show a significantly increased risk.

The researchers also looked at data relating to the clinical severity and onset of PE, and report that the familial associations were stronger for severe or early onset pre-eclampsia. The increased risk of parenting a pregnancy affected by severe PE was threefold for mothers and almost two-fold (1.9) for fathers born after pre-eclamptic pregnancies.

Although the relative risk factors reported in this study are modest, the results are based on data from a large population, including almost eight thousand parents who were themselves born following a pre-eclamptic pregnancy, making them likely to be fairly accurate. The authors do note the possibility of the data being influenced by confounding factors, but report that analysis of confounding factors using the more detailed data available from 1999-2003 did not show any evidence of a substantial influence on the risk factors. Confounding factors could include obesity, maternal age, dietary factors and smoking in pregnancy; as with all complex genetic disorders, it is very difficult to identify the genetic factors at work due to the presence of multiple environmental influences.

Comment: This study lends weight to previous proposals that there are both maternal and fetal genetic factors that may predispose towards pre-eclamptic pregnancy, especially severe forms of pre-eclampsia. Maternal family history has the greatest influence on PE risk, but paternal family history of the condition can also contribute. Although the relative risks of pre-eclampsia in pregnancies where the grandmother suffered from PE suggested by this study are small, they could nevertheless be significant in assessing risk for individual pregnancies.

The UK Pre-eclampsia Community Guideline (PRECOG), issued earlier this year, include an assessment tool for doctors or midwives to identify women at increased risk of pre eclampsia early in pregnancy, by identifying predisposing factors. These include “Family history of pre-eclampsia (in mother or sister)”. If further evidence supports the results of this paper, it could merit the widening of this category to include the family history of the male partner, as well as the pregnant woman.

2 November 2005Population-based family studies in genetic epidemiology. Hopper JL, Bishop DT and Easton DF (2005) Lancet 366, 1397-1406. Sixth in a series of summary pieces on aspects of genetic epidemiology.

Genetic epidemiology and public health: hope, hype and future prospects. Davey Smith G et al. (2005) Lancet 366, 1484-1498. Seventh and final article in a series of summary pieces on aspects of genetic epidemiology.

Molecular genetics goes to the diabetes clinic. Hattersley AT (2005) Clinical Medicine 5, 476-481. Lecture-based article on the use of molecular genetic testing for diabetes diagnosis.

Genetic predisposition to cancer. Turnbull C and Hodgson S (2005) Clinical Medicine 5, 491-498. General review, focusing on breast and colorectal cancers.

MicroRNAs as oncogenes and tumor suppressors. Chen C-Z (2005) N Engl J Med 353, 1768-1770. Perspective article on microRNAs, a class of small RNAs involved in the regulation of gene expression, and how they have been implicated in cancer.

The distinctive nature of HER2-positive breast cancers. Burstein HJ (2005) N Engl J Med 353, 1652-1654. Perspectives article on HER2 and the use of trastuzumab in breast cancer treatment, including the potential to discriminate between classes of breast cancer via genomic profiling.

On genes, speech and language. Fisher SE (2005) N Engl J Med 353, 1655-1657. Perspectives article on genetic influences on the normal development of speech and language.

There are several commentaries on human genome information following the recent publication of new data from the International HapMap Project, including:

Patchwork people. Check E (2005) Nature 437, 1087-1086. News feature.

Deeper into the genome. Gibbs R (2005) nature 431, 1233-1234. Commentary proposing that a large-scale human genome project should follow the HapMap initiative, to catalogue the rarer genetic variants that affect health.

Understanding human diversity. Goldstein DB and Cavalleri GL (2005) Nature 437, 1241-1242. News and views piece on how data from the HapMap project can be used to advance understanding of how genetic variation influences health.

Genomic cartography – presenting the HapMap. Phimister EG (2005) N Engl J Med 353, 1766-1768. Perspective article.