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NGS Leaders Blog

Guest Post: International Crowdsourcing Initiative to Combat the E. Coli Breakout in Germany

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June 8, 2011 

Editor’s Note: In light of the recent E coli outbreak in Germany, NGS Leaders invited Joyce Peng from BGI to comment on the organization’s efforts to understand the culprit. Below Joyce describes BGI’s efforts to rally the international community in combating the outbreak. – Eric Glazergenome sequencing 

In response to the recent E. coli outbreak in Germany, BGI and its collaborators at the University Medical Centre Hamburg-Eppendorf have released their third version of the assembled genome, which includes new data from this E. coli O104 (ftp://ftp.genomics.org.cn/pub/Ecoli_TY-2482/Escherichia_coli_TY-2482.contig.20110606.fa.gz ). The FTP site contains a file that provides the PCR primer sequences which researchers have used to create diagnostic kits for rapid identification of this highly infectious bacterium.

Bioinformatics analysis revealed that this E. coli is a new strain of bacteria that is highly infectious and toxic. BGI and its collaborators, as well as a growing number of researchers around the world “crowdsourcing” this data, are exploring in depth the European disease outbreak and helping to trace the origin and spread of the lethal E. coli strain. The latest evidence is that a previous 2001 German strain is the most likely ancestor of the current strain, perhaps suggesting that a fast evolution resulted in the gain of more genes over the last 10 years. Further comparisons between the genomes of these bacteria will clarify why the latest outbreak has been so exceptionally pathogenic, and help frontline healthcare workers fight to control this new global outbreak.

Unfortunately the 2001 German strain currently has no publicly available genome sequence, although it was preliminarily analyzed during the original outbreak and stocks and samples were hopefully stored. In the great strides already made in just a few days by the community from sharing original genomic data, BGI has made an appeal to any labs which have isolates of this key strain to share samples and respective data.

The international community “crowdsourcing” and analyzing BGI’s most up-to-date genomic data now has a repository for this preliminary data, and BGI encourages scientists to use its latest improved assembly (http://www.ncbi.nlm.nih.gov/bioproject/67657) and follow the repository and its Twitter feed (@BGI_Events) for announcements and data updates https://github.com/ehec-outbreak-crowdsourced/BGI-data-analysis 

BGI and the Beijing Institute of Microbiology and Epidemiology researchers have also developed a straightforward PCR diagnostic protocol for rapid identification of the outbreak strain. The diagnostic method consists of two pairs of amplification primers that target the enteroaggregative- and hemorrhagic-associated genes (more detailed protocol is available on the BGI FTP site). Diagnostic results can be obtained within 2–3 hours after receiving the sample, and thus will be extremely useful for epidemic surveillance and detection of the bacterium. The complete test protocol for E. coli O104 is available at ftp://ftp.genomics.org.cn/pub/Ecoli_TY-2482/Specific_primers_for_PCR_detection.pdf. In an effort to help control the spread of this lethal bacteria, BGI and the Beijing Institute of Microbiology and Epidemiology will provide the designed and synthesized primers free to any disease control and research agency worldwide.

This comparative work is now of the utmost urgency, so please contact BGI to collaborate in this effort by contributing samples or data from strain HUSEC041/01-09591 (contact caosujie@genomics.org.cn).

Joyce Peng, PhD is Marketing Director for BGI Americas Corporation (www.bgiamericas.com). She can be reached at joyce.peng@bgiamericas.com  

Why Should We Care About Next-Generation Sequencing (NGS)?

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Alexander Kamb June 1, 2011 

Alexander Kamb : It's hard to read the writing when you’re at the blackboard, but we seem to be in the midst of a revolution. If you step back, you can see how NGS may be more than mind-blowing technology—it may actually reignite drug discovery and transform medical practice.

Like the dawn of recombinant DNA, monoclonal antibodies and PCR, medical science may be poised—after a long pause—for another discontinuous jump forward. It’s taken a full decade and a radical new technology to illuminate the path from the human genome sequence.

The realization of personalized medicine 

When I went to the doctor recently with (as it turned out) a minor ailment, his first question was: Do you have any relatives who have had heart problems? Imagine the improvement in precision of diagnosis if he had access to my genetic risk profile! Different DNA sequence variants are associated with different disease risks, and in the coming years the quantitative implications of these risk variants, in whatever combination you happen to possess them, will clarify.

Challenges of interpretation, privacy, and basic genetic understanding will persist (the subject of a future blog), but the benefits of this type of information are progressively attractive. Sooner than later, a once-in-a-lifetime genome-sequence determination will be part of our health care system. At a cost of $1,000 (or less), individuals and their physicians will view personal genetic information alongside symptoms to increase the reliability of diagnosis. Furthermore, genome sequence will play an increasing role in drug prescription, helping to select one drug from a menu to improve the chances of patient-specific efficacy and avoid adverse reactions, including serious ones like life-threatening liver toxicities. This myriad of genetic data will be acquired for everyone in a single NGS assay, and will be flagged on our personal health records.

Cancer diagnosis and therapy hold a special place for the utility of NGS. Given the enormous quantity of somatic DNA change that NGS is currently unmasking, we may assume that in the future the relation between a patient’s tumor DNA and his/her normal germline DNA will inform which drugs are prescribed, and how tumor burden is assessed following therapy. If the tumor bears an activating K-RAS mutation, for instance, it is futile to use an EGFR antagonist since the pathway is short-circuited. Furthermore, as tumors wane, and then wax, it will be vital to track the genetic changes that account for this evolution, to give the oncologists solid guidance for their counterattack on the relapsed tumor.

New targets and disease mechanisms 

Human genetics has been a rich source of new targets and disease mechanisms; for instance, oncogenes and tumor suppressor genes in cancer. Now we have the power of N: the technical capacity and economics to look at millions of common variants across tens of thousands of patients, or to examine smaller sets of individual genomes at the highest resolution possible—the nucleotide. With NGS, we can identify rare variants with larger effects much more easily than before. And with other genotyping techniques we can identify and quantify small contributions of individual loci to disease risk. Since small effects on gene function may be amplified by good pharmacologic agents (i.e. drugs), we now have a burgeoning number of new avenues for mechanistic studies, and pending some follow-up work, drug targets.

Two recent examples from the fields of Alzheimer’s disease (AD) and schizophrenia underscore the prospects for the new genomics. For more than a decade the only known genetic risk factor for late-onset AD was the APOE4 allele indentified by Allen Roses and colleagues in 1993. But in the past couple of years, nearly a dozen new loci have been defined that implicate several new biological mechanisms in the disease process, including immune function and protein internalization. In genetic studies of schizophrenia this year, Sebat and coworkers reported that gene duplication and resultant overexpression of VIPR2 causes disease—the impetus for a direct assault on this GPCR as a potentially druggable target. The pace of medically relevant discovery is accelerating in challenging diseases such as these, and in others such as autism.

Fatigue—even cynicism--followed the failure of genomics to live up to its post-Genome Project hype. In anticipation of the first publications of the human genome sequence, many genomics companies were valued at billions of dollars apiece. When it dawned on investors that disease cures weren’t declaring themselves among the billions of base pairs, much of this value evaporated. Malaise set in. But in fact, the genome sequence was useful infrastructure—no more, but no less. At last we have the technologies to begin to exploit it. The coming decade will realize some of the original promise: new biological insights and better medicines.

Alexander Kamb leads the neuroscience division at Amgen. He is on the Advisory Board of NGS Leaders. Email: akamb@amgen.com 

OCT
10
I-Study: Genomic Interpretation - Who Will Pay?
During this webinar, members of the study review team present preliminary findings of the I-Study, conducted at the Harvard Medical School's 2011 Personalized Medicine Conference.
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