Hello, I'm the CTO and founder of Eagle Genomics, and Cambridge-based professional services company specialising in genome content management. I'd like to talk to you today about technologies emerging from genomics and computing and suggest how these can be applied to the study of phytomedicine.
It's been 10 years since the sequencing of the genome...Initial impact (Eric Lander) Genomic medicine will transform the health of our children and our children's children.One of the major advances has been our understanding of the genetic basis behind disease, significantly through the technique of genome wide association of genotypes, DNA differences between individuals, and observable traits (phenotypes).In this illustration, the central graph shows a region of 1million base pairs on chromosome 15, or 1 3-thousandth of the total genome. Each of the points on the graph is the location of a single base pair difference between individuals' DNA. Only a few 100s are shown here from several millions that will have been present in the experiment as a whole.The y axis is the probability that the genotype at each location is related to a specific phenotype, based on a sample of 18,000 individuals. So, in this case, what is the phenotype? Coffee consumption! Which is used as a model of addictive behaviour. The study itself was published this summer in the Journal of molecular Psychiatry - Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.So what do these genes do? CYP1A1 is the main caffeine-metabolising enzyme, and CYP1A2 metabolises other coffee aromatics. NRCAM is a neuronal cell adhesion molecule that has been implicated in addiction vulnerability.So what does this mean? The reference at rs2470893 is a C, and for each copy of T you will drink 0.2 extra cups of coffee/day. My genotype at this location is CT (23andMe), so I can blame a cup of coffee per week on my genes. However, the heritability of coffee consumption is about 50%, so I can blame quite a few more cups on my patents!
Pharmacogenomics is influence of genetic variation on drug response; i.e. correlation with pharmacological phenotypes.The idea is to use phenotypic association as the basis of a molecular biomarker. Patients that carry this biomarker can be given the right drug at the right dose at the right time.To date this approach has worked well for targeted cancer therapies such as Herceptin, not surprising as cancer is fundamentally a disease of the genome. And also Warfarin dosing. Such are the benefits to efficacy and ADRS, consideration of pharmacogenomics in drug development is becoming widely accepted within large pharma.
Let's bring in the plant side of the equation.One of the early and perhaps most advanced applications of the “new genomics” is in plant breeding.Here, you start with the a pedigree, the example shows rice plants from International Rice Research Institute in the Philippines.The phenotypes and genotypes of each plant are measured, and statistically associated.The associations are used to develop assays (biomarkers) for desirable phenotypes (disease/drought resistance, increased yeild)These assays are used in plant breeding programmes to select the individuals to take forward
So what has plant breeding to do with phytogenomics? Great example: the sequenced model plant, Medicagotruculata, being used to study the biosynthesis of an important class of medically-significant compounds, namely Saponin. A ready and therapeutically relevant example is the cardio-active agent digoxin, from common foxglove.Saponins possess a range of biological activities, including antimicrobial, anti-palatability, anti-cancer and hemolytic. But the biosynthesis of these compounds is not understood. Medicagotruncatula produces over 30 different triterpenesaponins. The Nobel foundation in Oklahoma are taking a functional genomics approach to identify and characterize various enzymes involved in saponin biosynthesis. Their strategy is to use gene expression analysis to provide candidate genes for further functional characterisation.Plants will then be selected to produce genotypes with altered saponin levels and composition. Transgenics (engineered genetic modification) will also be used.sition.[c] Another large class of phytomedicinal compounds, terpinoids, are being studied by researchers in Copenhagen, Denmark are using the model moss Physcomitrella patens, which also has a sequenced genome, as an alternative platform for production of terpenoid drug candidates. Terpenoid-based drugs have worldwide sales of over $12Bn,
High-throughput genomics techniques benefit greatly from the availability of a reference sequence for the species under study.Out of 30 published plant genome sequences, at least 4 species have studied phytomedicinal propertiesFrom the ancient...Cannabis sativa - Genome Published this Autumn (Oct 2011) Genome Biology Marijuana has been used medicinally for more than 2,700 years, and continues to be explored for its pharmaceutical potential.To the problematic...Aqualegia (columbine)Native Americans used root as an effective treatment for ulcers. But high toxicity; columbine poisonings may be fatal.To the trendy...Theobroma cacao - Genome Published last year (December 2010) Nat. Genet.Number of studies shown that cocoa can act to lower blood pressure, follow up studies pinpoint action as ACE inhibitor.To the hypothetical…Castor BeanThe castor bean (Ricinuscommunis) is an oilseed plant that is thesource of castor oil and the deadly poison ricin.Several medicinally-useful characteristics have been shown in models;- [leaf] hepatoprotective in rats.- [leaf] antimicrobial against pathogenic bacteria in rats.- [pericarp] improved memory consolidation in mice- [root bark] showed analgesic, antihistamine and anti-inflammatory properties in rats
Moving away from the plants and back to the humans; what does genomics provide in the target space?One of expectations of the genome was to empower Pharmaceutical companies to create drugs based on the DNA, RNA and proteins molecules associated with genes and diseases.The rate of progress has not been as fast as some pundits would have liked, hence recent flurry of expectation-setting exercises. The US National Human Genetics Research Institute, for insurance, suggests that most new drugs based on the completed genome are still perhaps 10 to 15 years in the future, although more than 350 biotech products - many based on genetic research - are currently in clinical trials.Some pharma co execs, notably Lilly's CEO John Lechleiter, are more bullish. He sees increased research productivity resulting a larger knowledge base. To quote from a recent xconomy article: "In some cases, our knowledge of biological pathways now is akin to lights being turned on in a room versus groping around in the dark.", Lilly continue to invest in R&D.The image for this slide is from Reactome, a curated database of biological processes in humans, and shows the many molecular actors in the apoptosis pathway.
So it is clear that pharmaceutical companies are now able to disentangle the mode of action for potential therapies more easily using genome information. The same premise follows for phytomedicine……More so if we consider synergy. Synergistic interaction means that the effect of two or more chemicals taken together is greater than the sum of their separate effects. A review published this summer in the british journal of pharmacology, suggests that phytocannabinoid-terpenoid interactions produce therapeutic synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infectionsPharmacodynamic synergy has been demonstrated between the various plant extracts traditionally combined in the treatment of malaria.How do you start to investigate these complex, multi-dimensional interactions? Unbiased assays looking at, for example, changes in genome-wide gene expression patterns would seem like a reasonable approach. Such studies are, indeed, starting to emerge, covered by a 2009 review in the journal "phytomedicine"
With the advent of "next generation" massively parallel DNA sequencing NGS), The cost of DNA sequencing has fallen a thousand-fold in the last three years, from $500/Mb to $0.5/Mb. This decrease in cost is truly democratising genomics; Data volumes that was previously only the domain of the largest international sequencing centres such as the Sanger in Cambridge or the Whitehead in the other Cambridge, are now available to even the most meagre labs. This has lead to an explosion in novel applications for NGS in genomics, transcriptomics, epigenomics, and metagenomics.
Whilst the cost of data generation has reduced dramatically, the bottleneck has become it's analysis, leading to this 2010 paper from WashU to speculate about the hoy grail of the $1000 genome being accompanied by a $100,000 price tag for analysis.New technologies = single molecule, (oxford nanopore)
Is lower potential TCO the only reason to go to cloud? No, trying to lower TCO is the wrong reason to move to cloud. Simple IT cost reduction should not be the only goal of a cloud implementation, says Kirwin. Just as important are other gains that can be achieved through cloud, including achieving heightened analytic processing of big data,- greater agility, - more flexibility, - faster time to market- improved business process
"No one can do it alone"The earlier graph on sequencing costs are reducing faster than with Moore's lawWith all the best will in the world, cloud is not going to fix it,"No one can do it alone"Can collaborate to address inefficiencies in pre competitive sequence and data services through;Pharma is moving to embrace open innovation model,
Rather than read this slide, I'll leave you with a quote from Greg Lucier, chief executive officer of Life Technologies (ABI);"From a simple return on investment, the financial stake made in mapping the entire human genome is clearly one of the best uses of taxpayer dollars the U.S. government has ever made" I challenge you to think of ways you may make use of it in your own enterprise.
1. Can genomics, facilitated by NGS and cloud computing, enhance phytomedicine in early stage R&D?Will Spooner, CTO, Founder, Eagle Genomics LtdWilliam.firstname.lastname@example.org
2. Phenotype Association Scientific impact of genomicsImage: Sartrhttp://sartr.deviantart.com/gallery/?offset=96#/d1u0z75 CC BY-NC-ND online publication 30 August 2011; doi:10.1038/mp.2011.101 Molecular Psychiatry advance 3.0
4. Genomics in plant breeding Germplasm/PedigreePhenotype Genotype Phenotyping Genotyping Phenotype/Genotype association Assays Breeding
5. Plant models for lead optimisationPhyscomitrella patens Image By: Ralf Reski CC BY-ND Image By: G. Nicolella http://luirig.altervista.org/cpm/albums/bot-002/normal_medicago-truncatula3637.jpg CC BY SA
6. Sequenced phytomedicinal plantsCannabis sativa Image By: Actv [CC] Aquilegia coerulea Image By: Eric LyonsTheobroma cacao Image By: Kai Yan, Joseph Wong [CC] Ricinuscommunis Image By: Howard F. Schwartzs [CC]
7. Genomics in research productivity Apoptotic execution Phase
8. Synergy in phytopharmacology 2 + 2 = more
9. NGS - democratising genomics
10. The Cost of Big Data Now Soon
11. Cloud Computing = Greater ScalabilityCloud Computing = Lower Cost+ Greater agility+ More flexibility+ Faster time to market+ Improved business process Image: PictureGirl http://pixdaus.com/single.php?id=256700 CC-BY-SA
13. Ensembl as a GCMS Leveraging Public Resources DAS Data Integration Data Querying Assembly/Genes httpd Data Reporting Variation Data AnalysisFunctional Genomics Data Integration APIComparative Genomics Data QC
14. Summary• Genomics is revolutionising: – Basic research, – Plant breeding, – Pharma R&D• Genomics can be applied to phytomedicine: – Lead discovery/optimisation, – Study of mode of action/synergy• Genomics R&D is empowered by: – NGS, – Cloud computing, – Open innovation.
15. Questions and Comments William.email@example.com ON EMAIL @wspoonr ON TWITTERExcept where otherwise noted, this work is licensed under the Creative Commons Attribution 3.0 License