A genome’s got to know its limitations

The U.K. government has become the latest believer in thegenome. In December 2012, the prime minister (PM) of the United Kingdomannounced an ambitious plan to fully sequence the genomes of 100,000 Britonswith cancer and rare diseases. The PM says: "hundreds of thousands ofbusinesses … are built on top of the Apple App Store, and we want to see theemergence of genomic platforms in the U.K. that similarly support the emergenceof new companies and innovations."

Although we are also believers in genomics, we suspect thatit will take the conventional 20 years or so between investment in research andcommercial exploitation. We also feel that application of genomics tohealthcare delivery will take place by a large number of small steps, and notas a big bang. In short, a genome's got to know its limitations.

The current state-of-the-art technology reminds me ofneuroscience in the 1970s, when we were using microelectrodes to read theelectrical activity of single neurons.

Unfortunately, both the technology of the time and ourless-than-perfect technique often yielded poor results—noisy signals that werea composite of many cells' asynchronous activity, aptly dubbed "CombinedRecording of Action Potentials (CRAP)."

Indeed, efforts of the day tounderstand brain function through microelectrode studies were consideredanalogous to investigating the workings of a computer armed with a set ofcrocodile clips and a voltmeter. The question is, are we doing something verysimilar in the headlong rush to sequence whole genomes from a myriad (or inthis case, ten myriads) of patients? Consider the following complications:

1. Cancer is dynamic. Taking a tumor sample and sequencingit gives you a snapshot, and expecting this to provide the basis forunderstanding disease progression is like cutting a frame out of a movie andtrying to predict what happens next. The value of the snapshot is inhypothesis-building, not the panacea in itself.

2. Cancer is highly heterogeneous, even between cells in asingle tumor deposit. Will we be sequencing DNA extracted from >1 cell(think neuroscience CRAP, above), or will we sequence a single cell (in whichcase, how do we make sure it will be representative of the overall disease)?This may delay or limit the "molecular pharmacy" concept that envisions cancercures achieved by combining several very specific inhibitors to match thegenomic profile of a tumor.

3. Pathways are complex with multiple branches, loops and ahigh level of redundancy. It's very tempting to overestimate the potential ofgene mutation discoveries, e.g., the2005 finding of the recurrent unique acquired clonal mutation JAK2V617F inmyeloproliferative disease. As a candidate cancer-driving mutation, it waslogical to create JAK2 inhibitors in the hope for a cure, only to find, atbest, symptom relief in the clinical setting. Complications lie in mutationsupstream and downstream of JAK2, many of which are "private" or unique to anindividual tumor. That's not to underplay the importance of understanding theJAK2 pathway, it's just that it may take 20 years for that discovery to come togenuine fruition as the surrounding biology is unraveled.

4. The larger the database, the greater the bioinformaticschallenge. A 100,000 whole-genome dataset will be so complex—and thiscomplexity will be magnified manifold when other public domain databases arebundled—that there are bound to be vast numbers of correlations with clinicalobservations, including many spurious ones. Such data dredging, bias orconfounding is well-known in epidemiological studies, and according to DouglasMerrill, former chief information officer and vice president of engineering atGoogle, "With too little data, you won't be able to make any conclusions thatyou trust. With loads of data you will find relationships that aren't real."

Moreover, the quality of the database and its curation arecrucial, and the detail of the clinical information associated with eachpatient is pivotal. Smaller, higher-quality datasets will be much morevaluable, and this is where private investment is sensibly focused.

5. Lastly, genotype is the key to clinical management and/ordrug-hunting currently only in a very small number of situations. The posterchild, Kalydeco (launched 23 years after the discovery of the underlyingmutation), was molecularly designed to treat patients with the G551D mutation(~4 percent of cystic fibrosis patients). But most diseases are multi-gene anddriven by a complex interplay with environmental and behavioral factors. Wehave made steps to an age where diseases aren't diagnosed by phenotype ("breastcancer"), but by their molecular pathology (HER2/neu amplification), and theseare still baby steps. In his 10th annual National Human Genome ResearchInstitute Trent Lectureship address, Bert Vogelstien said, "the study ofgenetic alterations in tumors will eventuallybe able to add quite a bit to standard, conventional histopathologicalanalysis" [emphasis added]. Major progress toward molecular pathology willrequire not only genomics, but also epigenetics (inherited changes in thegenome caused by factors other than DNA sequence changes), transcriptomics,proteomics, kinomics and metabolomics, conducted in longitudinal studies in parallelwith meticulous clinical characterization, and banking of samples for all ofthe as-yet undiscovered 'omics studies that future generations will hail as"the key."

So while we should not pack up our tents and move away fromgenomics, we should integrate it into an intelligent framework. There isalready a vast amount of cancer genome sequencing in progress, and we need tomake sure that newly funded work is genuinely additive. Let's not just buildever-more spectacular haystacks of data and then send an army ofbioinformaticians off to find the needles. Fishing expeditions do not have agreat track record in drug discovery (witness the spectacular fail ofcombinatorial chemistry and high-throughput screening). Genomics is no more thesingle answer than it was when some enthusiasts hailed the 1999 deal betweenHuman Genome Sciences ("they have all the targets") and Cambridge AntibodyTechnology ("they have all the drugs").

The Apple App Store was built within a five-year period;genomic "apps" will take a lot longer, maybe 20 years or more. After all, thegenome's got to know its limitations.

Anthony Walker is a partner at Alacrita Consulting, atransatlantic advisory firm providing expertise-based consulting services tothe pharmaceutical, biotechnology and life-science sectors. His experienceincludes due diligence, technology and market appraisal, business planning andstrategic management. Previously, Walker was CEO of Onyvax Ltd., abiotechnology company developing cancer vaccines.

Cambridge Antibody Technology