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30 November 2007Two companies have recently launched direct access whole genome scans, and more are planning to introduce similar services in early 2008.

 

Icelandic company deCODE Genetics was the first into the market with deCODEme, launched on 16th November 2007. This was closely followed by the Californian company 23andMe, which together with its influential and somewhat ubiquitous partner Google, announced a similar service just 3 days later. Both companies use a microarray to analyse hundreds of thousands of single nucleotide polymorphisms (SNPs) in DNA taken from a saliva sample, in order to predict susceptibility to dozens of different traits and diseases. The service costs around $1,000, which includes a password-protected internet site for customers to explore their data, and the companies emphasise that they are providers of genetic information, not medical diagnoses. Another two US companies, Navigenics and Knome, are preparing to launch similar but more medically oriented services early next year.

 

Consumers will learn how their lifetime risk of contracting a number of complex diseases – including Alzheimer’s disease, coronary heart disease, type II diabetes and prostate cancer – varies from the baseline population risk. In theory, this information will empower the individual to take control of their own health by making smart lifestyle choices. However, whilst these developments undoubtedly represent a huge leap forward in personalised genomics, there are serious questions regarding translation of the information directly into personalised medicine or individualised health plans. Estimating the individual risk of a complex disease, which involves the interplay of multiple genetic, epigenetic and environmental factors, is currently near impossible based on genetic data. The network of gene-gene and gene-environment interactions that moderate the effect of individual gene variants are largely unknown, and many of the correlations between specific SNPs and disease are far from being proven at an individual level. Whilst some correlations are weak, derived from small studies with insufficient power to draw statistically significant and reproducible conclusions, many of those that have been validated by large studies or meta-analysis make only a very small contribution to the overall risk of getting a disease.

 

As a result of these complications, European guidelines were recently unveiled stipulating that genetic tests should only be used under medical supervision (see previous news article). But how many doctors understand how to interpret the results of these tests for an individual? And whilst the companies promise to accept customers anonymously, issues of informed consent and privacy still loom large over this entire field.

 

Although much good may come from these new services, all but the most savvy consumer should be wary of accepting false truths. Without valid interpretation, personalised genomics could be, at best, a waste of time and money, and at worst, wholly misleading and potentially damaging.

29 November 2007Advisors to the UN have called for an urgent international prohibition on the reproductive cloning of humans. In the UK, as in more than 50 other countries, national law forbids the cloning of humans for the purposes of reproduction. In a report issued on 10th November 2007, the United Nations University’s Institute of Advanced Studies (UNU-IAS) says that the proposed ban is intended to prevent "unscrupulous scientists" from taking their research activities to countries that impose no legislative barriers to it.

Previous attempts at international agreement in favour of a total ban on human cloning have failed, despite a common belief that a legal prohibition on reproductive cloning was desirable. The absence of consensus was attributable in part to the complex and controversial questions surrounding cloning for therapeutic research purposes, a matter that is permitted in the UK (subject to strict regulation via the Human Fertilisation and Embryology Authority (HFEA)) but remains illegal in many other countries. As a result, in 2005 the UN issued a non-binding Declaration that called for a ban on reproductive cloning, but failed to address therapeutic cloning (see previous news), a compromise that was considered by some to be an inadequate response (study co-author Brendan Tobin: see Reuters news).

The report, Is human reproductive cloning inevitable: future options for UN governance, claims that, in the absence of international action, research “jurisdiction shopping” and reproductive cloning are inevitable, and will necessitate the development of policies and programmes for the protection of the human rights of cloned individuals.  Nevertheless, it sets out various approaches to regulation in the field, including the imposition of a total ban on cloning, and a ban on reproductive cloning (with or without full permission or trial permission for therapeutic cloning research).

It is unlikely, however, that the fundamental differences over therapeutic cloning will have altered significantly since the last round of negotiations. Despite being urged by the UN to find a new position “that allows for adoption of a respected and effective mechanism to govern human cloning”, lack of international consensus may once again prove an effective barrier to a global prohibition on reproductive cloning.

21 November 2007The prospect of creating cloned stem cell lines from the cells of adult humans appears to have moved a step closer with a report in the journal Nature of the generation of two such cell lines from a primate – in this case, an adult rhesus macaque.

 

Previously, somatic cell nuclear transfer (SCNT), which involves replacing the nuclear genetic material of an unfertilized egg with that of a somatic cell, has been used to produce embryonic stem (ES) cell lines from mice. When studying SCNT in rhesus macaques Byrne et al. noticed that the lack of sucess in dedifferentiation of cells to an embryonic, pleuripotent state using this technique correlated with a prematire decline in the activity of maturity activating factor, which is responsible for remodelling of the nuclear skeleton.

 

They used this information to develop a species-specific modification of SCNT that prevents the decline in maturity promoting factor. This enabled them to generate two ES cell lines from the skin cells of a male rhesus macaque, although the authors themselves note that, even with the modification, the efficiency of this process is still low (0.7%). At present, it is also not know whether this modification is effective when using SCNT to derive human ES cells.

 

The results have been verified independently in an accompanying report that analyses mitochondrial and genomic DNA in the two resulting stem cell lines, confirming that they originate from the two female oocyte recipients and the male cell nucleus donor, respectively.

 

Generating patient-specific stemcells to create replacement tissue that will not be rejected by the recipient is considered to have great promise for individualised medical therapy. However, in a related commentary, Ian Wilmut and Jane Taylor consider that the resources needed to use SCNT to produce differentiated cells for such purposes would make this impractical. Rather, they envisage that such human ES cell lines are likely to have greater value in basic research into inherited diseases, and in drug discovery and development.

 

 

 

 

14 November 2007Following the launch of a commercial service to harvest and store stem cells from excess IVF embryos (see previous news), another US company is offering a new service to women to harvest and store stem cells from menstrual blood samples. The charge is significantly lower than for cord blood or embryonic stem cell banking at around £238 for processing and a year's storage, and company Cryo-Cell claims this approach is less invasive than other forms of stem cell banking, but stem cell experts have condemned their service as premature and exploitative. The company itself acknowledges that "realistically, it may take several years for these menstrual stem cells to be developed into potential widely-available commercial therapies", whilst asserting that stem cells in menstrual blood have all the properties required for regenerative medical applications. However, Professor Peter Braude of King’s College London told the BBC: "This is all hypothesis and hype. This is such a long way off…The thing that worries me most is that it is capitalising on people's insecurity" (see BBC news).

9 November 2007New genotypic data from families affected by autism (autistic individuals plus their parents and siblings) have been released by the Autism Consortium, a US alliance that seeks to bring together families, clinicians and researchers to drive research into autism and potential treatments. It is thought that genetic factors may play a significant role in the development of autism and related disorders, which show a familial tendency with a raised risk of disease for the siblings of affected children.

DNA samples provided by the Autism Genetic Resource Exchange, a programme dedicated to accelerating the pace of autism research that dubs itself ‘a collaborative gene bank for autism’, were used to complete “the first genome scan for Autism Spectrum Disorders (ASD)” (see press release). Rather than keeping the data to themselves while they analyse it for potential genetic links to the conditions, the group say that they are releasing the genotype data to allow other researchers to scrutinize it, on the basis that the more research it generates the better, in terms of advancing understanding of the genetic contributions to autism. President of the Autism Consortium Peter Barrett commented:  “when people work together toward a common goal, we can speed up our understanding of these disorders and move towards better ways to help individuals with autism spectrum disorders and their families”.

8 November 2007The US Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) has released a draft report for the Secretary of Health and Human Services (HHS) on the assessment and regulation of genetic testing, and is inviting public comments on the report.

The report is the result of an enquiry that began in March 2007 to determine “the steps needed for evidence development and oversight for genetic and genomic tests, with improvement of health quality as the primary goal”, in particular to assess how far the validity, interpretation and utility of such tests for clinical and personal decision-making was being checked, and to assess whether there were gaps in the current system of oversight that might result in harms to public health. At the same time, the HHS launched the Personalized Health Care Initiative, a scheme intended to advance the integration of genomic technologies that are capable of tailoring preventative strategies and interventions to “each patient’s unique genetic characteristics and individual needs into general”.

The main recommendation of the report is that the HHS should “enhance interagency coordination of the activities associated with the oversight of genetic testing, including policy and resource development, education, regulation, and knowledge generation”.

The enquiry found that current oversight of genetic testing in the US is patchy, provided by different government agencies, professional associations, health insurers and other groups (or not at all) for different sorts of test. The report notes the increasing levels of direct-to-consumer advertising of genetic tests, combined with very limited access to genetics expertise for patients as well as consumers in general, calling for increased provision of trained genetics advisers. The report also noted a lack of evidence on the clinical utility of genetic tests, and called for the HHS to fund such assessments and develop clinical guidelines for the use of such tests, building on the CDC’s Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative (see previous news). Insurance companies were noted to typically require such evidence before agreeing to cover the cost of testing.

The draft report concludes that increased regulation of genetic testing is required, especially since more recent applications such as nutrigenomic tests and fetal gender testing are "skirting the boundaries" of current regulation; it calls for expansion of the Clinical Laboratories Improvement Amendments of 1988 to include more provision of expert assessment and proficiency testing for genetic tests. It also says that other government agencies including the Centers for Disease Control and Prevention and the Food and Drug Administration should increase scrutiny of laboratories, working in partnership with private companies, and take action against any that make misleading claims for genetic tests. A voluntary system of genetic test registration through a public-private partnership is proposed, expanding the current GeneTests system (a publicly funded medical genetics information resource for healthcare providers) to include broader genomic applications such as pharmacogenomic tests, with ongoing assessment of compliance with this system and a move to mandatory registration if necessary.

Comments on the report can be made at a SACGHS meeting on November 19-20 or submitted via email; the consultation period closes on 21 December. Input is specifically requested on whether the draft report adequately fulfils the committee’s original brief, whether it proposes adequate measures to improve the current regulatory system for genetic tests, and whether it adequately anticipates future developments in genetics and genomics.

1 November 2007A new Australia-China Centre for Excellence in Stem Cell Sciences is to be established in a partnership between Monash University and Peking University (see press release). Monash Immunology and Stem Cell Laboratories (MISCL) have been awarded federal funding to set up the new centre as part of the Australian government's International Science Linkages programme; the Chinese government have matched the AU$1 million investment over three years. Researchers will study various aspects of stem cell biology including potential therapeutic applications against serious infections, autoimmune disorders and cancer.

26 November 2007In recent years, the age old debate of nature versus nurture – genetics or environment – and has shifted towards gene-environment interactions; how does our response to the environment vary with genetics? Recent research published in the Proceedings of the National Academy of Sciences indicates that the long established correlation between IQ and breastfeeding is moderated by genetics [Caspi A. et al. (2007) PNAS 104: 18860-18865].

 

A strong link between breastfeeding and increased IQ was established a decade ago, and appeared to highlight the importance of non-genetic, environmental factors in determining intelligence. Researchers at King’s College, London investigated whether this correlation had any genetic basis by focussing on a single gene (FADS2) which encodes an enzyme involved in the conversion of dietary fatty acids, like those found in breast milk, into polyunsaturated acids, which accumulate in the developing brain. Specific polymorphisms in FADS2 were genotyped in over 2,700 members of two separate birth cohorts and compared against IQ, breastfeeding history and a number of other potentially confounding factors.

 

Interestingly, whilst there was an increased average IQ in those who had been breastfed, this correlation was limited to individuals possessing one or two copies of a particular allele for FADS2. However, no significant difference in IQ with breastfeeding was observed in individuals who were homozygous for a different allele. Although the molecular mechanism behind this finding is unknown, the authors speculate that it maybe due to more efficient fatty acid metabolism resulting from one of the FADS2 alleles. This study supports a unified model of genetics and dietary fatty acids in neural development and may result in a call for nutrigenomic studies to inform the further development of infant formulas.

 

Comment: Although a great deal of work has been performed on the genetic basis for intelligence, accompanied by much public interest and media hype, genetic variants such as these are unlikely to be uncovered by standard genome-wide association studies as their effect is conditional upon particular environmental exposures. This study contributes to the small but growing number of known gene-environment interactions and highlights the difficulty of uncovering genes involved in complex traits and diseases.

21 November 2007Two independent studies published online simultaneously in the top journals Cell [Takahashi K et al. (2007) Cell doi: 10.1016/j.cell.2007.11.019] and Science [Yu J et al. (2007) Science doi: 10.1126/science.1151526] describe the production of stem cells from human adult skin cells. This is the first time that pluripotent stem cells, which can differentiate into any adult cell (but not the placenta), have been produced from human adult tissue, although research published just a week previously described the production of stem cells from the skin of an adult rhesus macaque (see previous news article).

 

Differentiation of primal stem cells into specialised cells during development is dictated by epigenetic rather than genetic events and is therefore, in principle, reversible. Epigenetic changes include DNA methylation at cytosine residues as well as modifications to the histone proteins that form the scaffold around which the DNA is wound, resulting in heritable changes in DNA accessibility and gene activity.

 

The teams of researchers at Kyoto University in Japan and the University of Wisconsin, Madison in the United States both used a technique known as nuclear reprogramming to remove this epigenetic code and return the cells to an undifferentiated state. Remarkably, the addition of just four transcription factor genes into the nucleus of adult skin cells is sufficient to reverse the differentiation process and cause the cells to revert back to stem cells. After successfully demonstrating that the cells looked and behaved very much like human embryonic stem cells, the researchers went on to differentiate the cells into cardiac cells, which began spontaneously beating after 12 days, as well as neural and gut epithelial cells.

 

Although these results come tantalisingly close to the realisation of regenerative medicine, the technique currently relies on a retrovirus to insert the transcription factor genes which presents a potential hazard to human health. Therefore further work is needed to find alternative methods of nuclear reprogramming prior to use of these so-called “induced” pluripotent stem cells in humans.

 

Comment: Direct reprogramming of terminally differentiated cells from adult humans into undifferentiated stem cells with the capacity to differentiate into any cell in the body is considered by many to be the “holy grail” of stem cell research. This work represents a huge leap forwards for the development of therapeutics derived from human stem cells particularly because skin cells could be taken from individual patients, therefore side-stepping problems associated with immune-based tissue rejection. If the work can be successfully reproduced and developed, it ultimately promises an end to the use of stem cells derived from human embryos and, with it, much of the political controversy and ethical debate surrounding this area of research.

19 November 2007In this year alone, at least five studies of genome-wide association studies of breast cancer genetics have been published uncovering numerous risk genes involved and highlighting the complexity of genetic susceptibility to multifactorial diseases such as cancer. A recent paper in Clinical Genetics summarises the genes discovered to date in connection with breast cancer and compares their relative importance in terms of risk [Williams PJ (2007) Clin. Genet. 72: 493-496].

 

Breast cancer is the most common of all cancers, with 44,000 women diagnosed every year in the UK (CRUK Cancer Stats). Women have a lifetime risk of around 1 in 10, but those with affected first degree relatives have double that risk, suggesting a strong genetic component. Since the discovery in the 1990s of the BRCA1 and 2 genes, where an inactivating mutation increases a woman’s lifetime risk to around 80%, mutations in many other genes have been discovered, each with differing degrees of penetrance. These can be broadly categorised into three groups:

(1)     High penetrance genes (BRCA1, BRCA2 and TP53) which increase the relative risk of developing the disease by 5-10 fold. However, variation in these highly genes accounts for only around 5% of breast cancer cases.

(2)     Intermediate penetrance genes (e.g. ATM, PALB2) increase the relative risk of developing disease by 2-3 fold. Like the high penetrance category, variation in these genes is relatively rare, occurring in less than 1% of the population.

(3)     Low penetrance genes (e.g. TGFB1, MAP3K1) identified by genome-wide association studies have recently been identified, which increase the relative risk of developing the disease by 1.1-1.3 fold. These variants are relatively common amongst the population but their contribution to the disease risk of a particular individual is currently unknown.

 

Because of the high baseline level of risk for this disease (approximately 10% lifetime risk for women), genetic variants that confer even a relatively small increase in risk might be important for screening purposes through population stratification. However, as Patrick Williams of the Genetic Diagnostic Network in Belgium and author of the review paper rightly points out, “the large number of anticipated susceptibility factors, their low predictive value and the high frequency of these variants in the population make these findings of limited use in clinical practice”.

 

Comment: This paper offers an unusually enlightened view of the current understanding and importance of breast cancer susceptibility genes. However, although low penetrance genetic variants may currently not offer high clinical utility, they increase our understanding of the molecular mechanisms involved in the development of cancer, which may play a crucial role in the development of novel therapies. For example, all the genes in the first two categories are involved in DNA repair, whilst those in the last category are implicated in cell growth and signalling, DNA transcription and apoptosis (programmed cell death), offering a several new categories of therapeutic targets. Comparison with genetic variants associated with other cancers may also shed light on the pathways that result in the development of one specific cancer rather than another. However, given the power of the large studies genome-wide associated studies already conducted, the utility of even larger studies aimed at uncovering ever more common but less clinically relevant genetic variants is unclear. 

7 November 2007An international team of scientists has published the first lung cancer genome in the advance online issue of the top science journal Nature [Weir BA  et al. (2007) Nature doi: 10.1038/nature06358]. The work was carried out as part of the Tumour Sequencing Project Consortium, supported by the National Human Genome Research Institute (NHGRI), which that aims to pilot approaches to large-scale identification of genomic changes in cancer tumours.

According to Cancer Research UK (CRUK), every year around 38,300 cases of lung cancer are diagnosed in the UK, leading to 33,500 deaths annually. It accounts for 13% of all cancers and 22% of all cancer deaths. The recent study focused on lung adenocarcinoma, a type of non-small cell lung cancer which accounts for around 30% of cases.

Over 350 anonymised tumour samples from lung cancer patients were analysed on a microarray for copy number variations relative to the reference human genome sequence. A total of 57 significant genomic changes that occur frequently in lung cancer patients were identified, including both significant copy number gains and loses, of which 26 were large-scale events of at least half a chromosome arm in size. The most common genomic alteration in lung cancer was found to be a copy number gain of chromosome 5p, present in over 60% of the samples. In total, the regions of common copy number gain (~650 megabases) and loss (~1,010 megabases) comprise more than half the entire human genome!

Despite these alarming changes, few of the large-scale events have been clearly linked to functional genes involved in cancer. However, of the 31 rare smaller amplifications and deletions characterised, one region on chromosome 14 which is amplified in 6% of samples encompasses two known genes, neither of which had previously been associated with cancer. Through additional cellular studies, the researchers established that one of the genes encodes a transcription factor essential for cancer cell growth and survival. 

Comment: Although most genome-wide association studies to date only analyse single nucleotide polymorphisms, the importance of larger structural variation is becoming clear. The findings of this study are supported by other recent research indicating that structural variation between individual genomes is highly abundant (see previous news article) and that alteration in the copy number of particular sequences makes a substantial contribution to differences in human and disease phenotypes (see previous news article). The application of systematic genomics to the investigation of genetic alterations associated with specific cancers is exemplified in this study. In addition to a better understanding of the incredible levels of genetic havoc wreaked by cancer, the discovery of a gene that is specifically active in certain cancer cells may have broad implications for the design of new cancer therapeutics.

5 November 2007Personalized Medicine in the Era of Genomics. Burke W, Psaty BM (2007) JAMA 298:1682-1684. Commentary offering useful ‘reality check’ on the real prospects for genomics in medicine, explaining that clinical practice has always had the aim of individualized care, and noting that genetic test information will simply  add an additional dimension to the spectrum of information and interventions that clinicians consider for each patient (PubMed).

Use and misuse of preimplantation genetic testing. Braude P, Flinter F (2007) BMJ 335(7623):752-4. Analysis piece contrasting the success of PGD with the lack of evidence to support prenatal genetic screening , looking ahead to possible future applications and the necessity to ensure the technique is only used with suitable medical justification (PubMed).

Pluripotency redux - advances in stem-cell research. Gearhart J, Pashos EE, Prasad MK (2007) N Engl J Med. 357(15):1469-72. Perspective piece reviewing recent developments in stem cell research (PubMed).

The 4th October issue of Nature has a special technology feature on genomics:

Genomics: the personal side of genomics. Blow N (2007) Nature 449(7162):627-30. Piece looking at the advances in sequencing and genotyping technology that are driving the pursuit of ‘personal genomics’ (PubMed). Followed by a series of brief profiles:

Genomics: Being Well Informed. Blow N (2007)Nature 449(7162):627 (PubMed).

Genomics: Truth and accuracy. Blow N (2007) Nature 449(7162):628 (PubMed).

Genomics: Chipping out our differences. Blow N (2007) 449(7162):629 (PubMed).

A matter of trust. Nature 2007 449(7163):637-8. Editorial piece calling for social scientists studying data protection to contribute to research on trust and scientific research, and proposing that abuse of personal data should be made a criminal offence (PubMed).

Ethical and legal aspects of cancer genetic testing. Offit K, Thom P (2007) Semin Oncol. 34(5):435-43. Review of ethical issues and legal liabilities associated with genetic testing for cancer (PubMed).

The Framingham Heart Study, on its way to becoming the gold standard for Cardiovascular Genetic Epidemiology? Jaquish CE (2007) BMC Med Genet. 8(1):63. Commentary accompanying articles on genome-wide association studies using data from the Framingham Heart Study (PubMed).

The 18th October issue of Nature has several features on personal genomics:

Do-it-yourself science. Nature 449(7164):755-6.Editorial suggesting that clinical geneticists will have to revise the professional and ethical framework for collaborating with patients and their advocates, now that so much genetic information is available to members of the public (PubMed).

So similar, yet so different. Check Hayden E (2007) Nature 449(7164):762-3. News feature on the possible impact in terms of disease risk and variability of very small sections of the human genome that show a high degree of variation between individuals (PubMed).

Personal genomics: His daughter's DNA. Maher B (2007) Nature 449(7164):773-6.News feature on a trained geneticist who set out to find the cause of his baby’s congenital defects for himself (PubMed).

Common sense for our genomes. Brenner SE (2007) Nature 449(7164):783-4. Commentary piece considering how a personal genome sequence could be of use if the means were available to properly interpret the information therein, and proposing the establishment of a public knowledge database of human genetic variation and its effect (PubMed).

Genetics. The science a