Firstly, apologies for the unannounced month-long sabbatical. I've recently moved house and set up shop in my new residence in Leeds, in addition to starting my summer studentship working on the wonderfully complex FCGR locus (its the copy number variation that makes it so complex btw). All this in combination with a little bit of first-blog burnout means I've been far too lax of late.
So I thought I'd return from self-imposed exile with a little bit of a discussion of a short article published online in the Financial Times. An article written by a GP in Glasgow in which she claims that personalized medicine is just a load of hype. This got me thinking a little bit, is personalized medicine truly hype, or is their really hope for a health-care revolution? Naturally I'm a little bit biased in favour of personalized medicine, afterall I'm due to start a PhD in pharmacogenetics this coming October, so there is a little bit of vested interest in the field, as I feel that it truly can revolutionize global healthcare.
So to the article in question first of all. Dr McCartney expresses her opinion that the genomic medicine revolution is all hype because of its inherent uncertainty. I'd say that is a valid point to make, after all the known genetic associations to date are largely of very small effect sizes; odds ratios in the range of 1.2-1.6 for most associated variants. She also mentions that smoking is one of the biggest, if not the biggest, risk factor for developing lung cancer, and thus the environment has a very important role to play. Another perfectly valid point. So why am I so bothered about this article? Well, it's because of what she doesn't mention, and qutie markedley leaves unsaid. The interactions between our genome and our life-time environment are very complex and poorly understood. That is not a valid reason to malign personalized medicine when it has not even reached its infancy. The current known associations have very little clinical utility because of their small effect size and individual minor influence. Their possible interactions, that is geneXgene interactions, have not even been fully investigated. Who is to say that a panel of 50 genetic markers doesn't have clinical utility? I'm not saying that it definitely will, but we cannot say until such time that this route is explored in a rigorous and meangiful way.
Dr McCartney goes onto point out the pitfalls of HER2 testing as a predictor of response to Herceptin (trastuzumab). Lack of sensitivity and specificity in a single test that relies on histology is not a basis for lambasting all of personalized medicine. Response to Herceptin is likely under the influence of other genetic loci, after all there are pharmacodynamic factors to take into account alongside the usual clinical covariates of disease stage, patient age, BMI, dosage, etc that must be taken into account. Afterall, personalized medicine is about the individual thus we are going to need to incorporate as many individual factors into the equation as possible to individualise each treatment.
She concludes that we may run the risk of creating more problems if we rely solely on genetic determinants (that's a misnomer, but this is not the place to discuss genetic determinism), and that prevention is ultimately better than cure - well said. However, knowledge of our genetic make up is potentially a very useful tool in our arsenal against disease because it may highlight disease susceptibilities that we can overcome by manipulating our own environments, i.e. our lifestyles. Overall, I'd say that Dr McCartney has some valid points to make about what barriers we need to overcome to reach the personalized medicine era, others she does not mention (perhaps due to pre-publication editing), however, the article is simplistic and comes across as very naive and ill informed. After all, where is the mention of Warfarin dosing? The known genetic influence on hepatitis treatment? The role of the cytochrome P 450's and drug metablolism, not to mention adverse pharmacological reactions? These are some of the targets of personalized medicine, and pharmacogenetics. For instance ~30-40% or rheumatoid arthritis sufferers fail to respond to initial biologic treatment with anti-TNF therapeutics. Does Dr McCartney believe that a genetic understanding, in collaboration with biochemical knowledge of the influences on biologic treatment as a tool for predicting treatment response, thus saving the patient from months of uncertainty and further pain, not to mention the potential savings for the health service where a single course of ineffectual treatment can cost upwards of £10,000. Is that all hype?
We have not reached the personalized medicine era, we are still exploring the role of genetic susceptibility in disease and therapeutic response, but it is moving at a fast pace. I agree that perhaps we need to be a little cautious, not succumb to zealotry, this is people's lives at stake, but the potential benefits are staggering. Imagine being able to walk into a clinic in 10-15 years time and have the clinicians be able to predict any potential adverse side effects, and whether or not you are likely to need an altered dosage regime. That requires more than just a knowledge of the underlying genetics and biology, it requires political and societal changes, the implementation of an infrastructure that can support and utlise such vast quantities of information, not to mention the educational requirements for both physicians and the general public.
We do need to see both sides of the story with regards to decisions that affect something as important as our personal and societal health. A more balanced approach that investigate both the barriers still to overcome and the limitations is called for. Sometimes it does seem like there is only ever fanfare surrounding the predictions of personalized medicine, however, a closer read of the blogosphere shows that this fanfare is well measured with caution and an understanding of the pitfalls of predicting disease susceptibility.
Monday, 26 July 2010
Wednesday, 30 June 2010
Gene patents - stifling innovation?
There have been a couple of events that have spurred me into voicing my own opinions with regard to gene patenting. The first is the Myriad gene patent of BRCA1 and BRCA2 which was overturned some weeks ago, and is now being contested (hardly a surprise when there is such a monetary incentive!). The other is an interview with ex-UK HGP director, John Sulston, in which he lays out his own concerns about gene patenting. We have to remember he was around at the start of the idea of being able to patent a gene or genome, when Craig Venter started up Celera in a bid to beat the public sequencing effort to the prize, and thus charge researchers for the privilege of accessing our own genomes.
I’m a fan of open access and transparency in science, in fact I would go so far as to say that it is a necessity of good scientific practise, and upholds and empowers the scientific method and the concept of science itself. So the idea of patenting a gene, or its specific variants, which was not invented, and is present in numerous persons within a given population, is anathema to the open access and transparent nature of good scientific practise. It prevents researchers from unhindered research into the mechanisms of mutations within the gene in question, and the ability to use it for clinical applications, such as diagnostic indicators in disease, or as prognostic indicators of therapeutic response or adverse side effects.
This is one of the major problems that can crop up when some of the drivers of pharmacological research have financially vested interests, as is the case with Myriad and other pharmaceutical companies. Don’t get me wrong, this isn’t a dig at BigPharma, it’s a dig at the money-grabbers, bureaucrats and lawyers for thinking they could ever place a patent on a naturally occurring biological molecule. If they are going to patent something to protect their intellectual property, do it in a responsible manner that does not stifle progress and innovation in the name of financial gain. Patent the diagnostic test and specific protocol itself if needs be; surely that protects their intellectual property sufficiently?
Now, I’m not a patent lawyer (I once heard a talk given by a chap going through the training, I wouldn’t want to subject myself to that level of tedium and mind-numbing law-talk, despite the excellent remuneration), so I don’t know the inner-workings of patent law, and the loop holes and requisites required, but the Myriad patent case and others in Australia need to set a precedent that naturally occurring biological molecules, complexes and machinery are not patentable, and that any artificial or derived variations on the natural theme are shown to be, with sufficient supporting evidence, sufficiently different that they are unlikely to exist, or occur within nature itself.
That should rule out any unscrupulous companies trying to patent rare variants too.
I understand the importance of patents, I believe (correct me if I’m wrong here), the patent offices were originally set up to promote innovation whilst protecting the rights of the inventors themselves. So we need to keep that original basis in mind when we consider the patenting of biological materials. Will this patent promote, or stifle, innovation?
Gene patenting can only ever stifle innovation that arises from competition, thus it is untenable, and should be rejected outright.
I’m a fan of open access and transparency in science, in fact I would go so far as to say that it is a necessity of good scientific practise, and upholds and empowers the scientific method and the concept of science itself. So the idea of patenting a gene, or its specific variants, which was not invented, and is present in numerous persons within a given population, is anathema to the open access and transparent nature of good scientific practise. It prevents researchers from unhindered research into the mechanisms of mutations within the gene in question, and the ability to use it for clinical applications, such as diagnostic indicators in disease, or as prognostic indicators of therapeutic response or adverse side effects.
This is one of the major problems that can crop up when some of the drivers of pharmacological research have financially vested interests, as is the case with Myriad and other pharmaceutical companies. Don’t get me wrong, this isn’t a dig at BigPharma, it’s a dig at the money-grabbers, bureaucrats and lawyers for thinking they could ever place a patent on a naturally occurring biological molecule. If they are going to patent something to protect their intellectual property, do it in a responsible manner that does not stifle progress and innovation in the name of financial gain. Patent the diagnostic test and specific protocol itself if needs be; surely that protects their intellectual property sufficiently?
Now, I’m not a patent lawyer (I once heard a talk given by a chap going through the training, I wouldn’t want to subject myself to that level of tedium and mind-numbing law-talk, despite the excellent remuneration), so I don’t know the inner-workings of patent law, and the loop holes and requisites required, but the Myriad patent case and others in Australia need to set a precedent that naturally occurring biological molecules, complexes and machinery are not patentable, and that any artificial or derived variations on the natural theme are shown to be, with sufficient supporting evidence, sufficiently different that they are unlikely to exist, or occur within nature itself.
That should rule out any unscrupulous companies trying to patent rare variants too.
I understand the importance of patents, I believe (correct me if I’m wrong here), the patent offices were originally set up to promote innovation whilst protecting the rights of the inventors themselves. So we need to keep that original basis in mind when we consider the patenting of biological materials. Will this patent promote, or stifle, innovation?
Gene patenting can only ever stifle innovation that arises from competition, thus it is untenable, and should be rejected outright.
Sunday, 27 June 2010
The Weekly Round-Up
This week there have been several stories of note that I've not had time to blog about, so I thought I'd start a weekly round-up of interesting news pieces.
[1] Starting with the Sanger Institutes announcement of their own 10,000 genomes project. The WTSI is performing its own 10,000 genomes project, its aim to help uncover the various genetic elements that predispose to various diseases and disorders by full resequencing of 4,000 individuals, and the exomes of another 6,000.
[2] This announcement from the WTSI comes in the same week that the original 1000 genomes project announces its release of their pilot data, prior to the start of their database for public and research use.
[3] I've already covered this story, but it seems, to me at least, a step forward towards the implementation of clinical sequencing by the Royal Brompton Hospital
[4] An interview with Francis Collins in The Times about how he sees the future of genomic medicine panning out, with an emphasis on the hurdles still to overcome, including the education of physicians and the general public about personal genomics and personalized medicine.
[5] 23andMe have published their first paper in PLoS Genetics, a GWAS of various phenotypic traits. Whilst most of these may seem superficial (hair colour, eye colour, etc), it is their research framework that is the focus of this paper.
[6] Its 10 years since Craig J. Venter and Francis Collins stepped out on the White House Lawn with President Bill Clinton to announce the complete draft of the Human Genome.
There has been much speculation about the predicted impact of genomic medicine, and whether or not it has, or will be able to, deliver on all its promises. It's true that most of the general public won't have noticed the significant advances made in genomic medicine, but I think we are within 10 years of routine clinical sequencing and the start of an era in personalized medicine. Watch this space!
[1] Starting with the Sanger Institutes announcement of their own 10,000 genomes project. The WTSI is performing its own 10,000 genomes project, its aim to help uncover the various genetic elements that predispose to various diseases and disorders by full resequencing of 4,000 individuals, and the exomes of another 6,000.
[2] This announcement from the WTSI comes in the same week that the original 1000 genomes project announces its release of their pilot data, prior to the start of their database for public and research use.
[3] I've already covered this story, but it seems, to me at least, a step forward towards the implementation of clinical sequencing by the Royal Brompton Hospital
[4] An interview with Francis Collins in The Times about how he sees the future of genomic medicine panning out, with an emphasis on the hurdles still to overcome, including the education of physicians and the general public about personal genomics and personalized medicine.
[5] 23andMe have published their first paper in PLoS Genetics, a GWAS of various phenotypic traits. Whilst most of these may seem superficial (hair colour, eye colour, etc), it is their research framework that is the focus of this paper.
[6] Its 10 years since Craig J. Venter and Francis Collins stepped out on the White House Lawn with President Bill Clinton to announce the complete draft of the Human Genome.
There has been much speculation about the predicted impact of genomic medicine, and whether or not it has, or will be able to, deliver on all its promises. It's true that most of the general public won't have noticed the significant advances made in genomic medicine, but I think we are within 10 years of routine clinical sequencing and the start of an era in personalized medicine. Watch this space!
Thursday, 24 June 2010
Celebrating 10 years since the completion of the Human Genome Project
A new programme has begun on BBC Radio 4 called "The Age of the Genome" as a part of the 10 year anniversary of the completion of the the Human Genome Project. This ~30 mins programme is narrated by the Evolutionary biologist, and champion of public understanding of science, Richard Dawkins. Whilst most people will be aware of Prof. Dawkins for his some what vocal criticism of religion, he stands out in my mind as man who's priorities are what he calls "concious raising". This doesn't just apply to the criticisms of religion, but also, and far more importantly, to increasing the general publics understanding and appreciation of the work carried out by hard working physicians and scientists around the globe. In particular his book, The Selfish Gene, a book that for me had a large impact on my initial understanding of genetics during the first year of my undergraduate studies.
The programme itself is largely made up of interviews with the principle players in the Human Genome Project; Francis Collins, John Sulston, Craig Venter and sound bites from other emninent scientists, including James Watson. For those not familiar with any of these names, or only a passing familiarity, Francis Collins is the current director of the US National Institute of Health and one of the heads of the HGP. Craig Venter is a more household name, particularly in recent weeks with the construction of a cell with an entirely synthetic genome which has raised so much debate. John Sulston headed up the UK branch of the HGP based at the Wellcome Trust Sanger Institute in Cambridge, UK. And finally James Watson, one of the co-discoverers of the 3D structure of DNA, alongside the late Francis Crick and Rosalind Franklin.
The programme describes the process of Sanger sequencing, the technique that made possible the completion of the human genome, alongside other computational technological advances, including accurate sequence alignment and sequence construction. As is likely with any science programme involving RD, there is a discussion of the evolutionary implications of the HGP, including the comparisons with the nematode worm, Caenorhabditis elegans, and the surprising finding that our genome only contains ~20,000 genes (the current count from the 1,000 Genomes project is 21,370).
I'm personally looking forward to the continuation of this radio series, whilst it may not necessarily be a steep learning curve for myself, it will certainly give me invaluable hints into how to present scientific advances to the lay audience.
Episode one can be listened to below in the embeded player, or directly from the BBC Radio 4 Website.
The programme itself is largely made up of interviews with the principle players in the Human Genome Project; Francis Collins, John Sulston, Craig Venter and sound bites from other emninent scientists, including James Watson. For those not familiar with any of these names, or only a passing familiarity, Francis Collins is the current director of the US National Institute of Health and one of the heads of the HGP. Craig Venter is a more household name, particularly in recent weeks with the construction of a cell with an entirely synthetic genome which has raised so much debate. John Sulston headed up the UK branch of the HGP based at the Wellcome Trust Sanger Institute in Cambridge, UK. And finally James Watson, one of the co-discoverers of the 3D structure of DNA, alongside the late Francis Crick and Rosalind Franklin.
The programme describes the process of Sanger sequencing, the technique that made possible the completion of the human genome, alongside other computational technological advances, including accurate sequence alignment and sequence construction. As is likely with any science programme involving RD, there is a discussion of the evolutionary implications of the HGP, including the comparisons with the nematode worm, Caenorhabditis elegans, and the surprising finding that our genome only contains ~20,000 genes (the current count from the 1,000 Genomes project is 21,370).
I'm personally looking forward to the continuation of this radio series, whilst it may not necessarily be a steep learning curve for myself, it will certainly give me invaluable hints into how to present scientific advances to the lay audience.
Episode one can be listened to below in the embeded player, or directly from the BBC Radio 4 Website.
Wednesday, 23 June 2010
Clinical Sequencing in the UK
It would appear that one of the first exome-sequencing projects run by the NHS is being launched at the Royal Brompton Hospital in London. Their aim appears to be to associate rare and common variants with cardiomyopathies and the results of MRI scans.
This is quite a leap forward for clinical sequencing, but I wonder whether they may be a little premature? The costs of sequencing have been plummeting for the last decade, but the current technologies have their own cons as well as pros. Sure they're faster and generally more high-throughput; but they also generate shorter read lengths and are thus more prone to sequencing errors which makes in depth sequencing a must for accurate data requisition. Then there is the computational analysis and storage requirements. Next-gen sequencers generate Gb of data and require specific bioinformatic tools to deal with sequence alignment because of the short read length, as well as the IT infrastructure to deal with the sudden explosion in data quantity; 10,000 exomes is a lot of information to handle and store. I can only assume they have these tools and expertise in place. What of the variants that are not known to be associated with cardiac defects, yet predispose to it nonetheless? Are they going to assess these as well. Their press release talks of tailoring each patients treatment to their genotype - that is premature!
The pros are just as numerous as the cons. Complete exome-sequencing will be able to uncover the rare variants that are most likely to have a high impact on disease risk and severity. They will be able to compare high resolution imaging directly with genotypic data, as well as other clinical and phenotypic information collected by the medical staff. This project may well set a precedent for clinical sequencing in the UK if the predicted results are as spectacular as they could be. Oh and they are looking for volunteers, preferably ones with a family history of cardiomyopathy. If it weren't all the way down in London I'd be tempted to give it a whirl, as long as I could get a copy of the data back for myself - cheaper than DTC testing!
I will be intrigued to see what comes of this project. I personally wouldn't have predicted routine clinical sequencing for another 20 years, perhaps the Royal Brompton Hospital researchers might be able to bump that forward a little.
Edit: Royal Brompton Hospital Press Release
This is quite a leap forward for clinical sequencing, but I wonder whether they may be a little premature? The costs of sequencing have been plummeting for the last decade, but the current technologies have their own cons as well as pros. Sure they're faster and generally more high-throughput; but they also generate shorter read lengths and are thus more prone to sequencing errors which makes in depth sequencing a must for accurate data requisition. Then there is the computational analysis and storage requirements. Next-gen sequencers generate Gb of data and require specific bioinformatic tools to deal with sequence alignment because of the short read length, as well as the IT infrastructure to deal with the sudden explosion in data quantity; 10,000 exomes is a lot of information to handle and store. I can only assume they have these tools and expertise in place. What of the variants that are not known to be associated with cardiac defects, yet predispose to it nonetheless? Are they going to assess these as well. Their press release talks of tailoring each patients treatment to their genotype - that is premature!
The pros are just as numerous as the cons. Complete exome-sequencing will be able to uncover the rare variants that are most likely to have a high impact on disease risk and severity. They will be able to compare high resolution imaging directly with genotypic data, as well as other clinical and phenotypic information collected by the medical staff. This project may well set a precedent for clinical sequencing in the UK if the predicted results are as spectacular as they could be. Oh and they are looking for volunteers, preferably ones with a family history of cardiomyopathy. If it weren't all the way down in London I'd be tempted to give it a whirl, as long as I could get a copy of the data back for myself - cheaper than DTC testing!
I will be intrigued to see what comes of this project. I personally wouldn't have predicted routine clinical sequencing for another 20 years, perhaps the Royal Brompton Hospital researchers might be able to bump that forward a little.
Edit: Royal Brompton Hospital Press Release
Subscribe to:
Posts (Atom)