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January 01, 2011 (Vol. 31, No. 1)

Bullet-Train Biotech & Reality

As DNA Sequencing Becomes Industrialized, Translation to Patient Care Is Paramount

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    George L. Gabor Miklos, Ph.D.

    Rapid industrial-strength nucleic acid sequencing technologies are highlighting the challenges faced by the research, medical, legal, ethical, and direct-to-consumer genetic testing communities in personalized medicine.

    For example, who are the knowledgeable human beings who can explain to cancer patients—in a sensitive way—their best therapeutic option based on sequencing data from the churning genomic rubble of their life-threatening metastatic tumors? Who can confidently explain the disease risks faced by healthy couples, or their yet-to-be-conceived children, when those risks consist of an unknown summation of genetics and the myriad epigenetic effects of individual lifestyles?

    Such challenges are not to be feared; we simply need to intelligently apply ourselves to understanding the benefits and limitations of such data, while discounting media reports, such as those in Science, that the National Cancer Institute has a plan to eliminate suffering and death from cancer by 2015. We need clinical reality, not the peddling of patently false hopes that mislead desperate cancer patients and their relatives who are vulnerable to such errant nonsense.

    The commercial reality is that the powerhouses of semiconductor technology, pure chemistry, and raw computing power are making human genomes, their methylated derivatives (methylomes), and their RNA outputs (transcriptomes) a successful commodity. Sequencing factories are producing data at a speed that is unparalleled in the history of biology and generating a shockwave similar to the effects on the Vatican’s pigeons of the appearance of Galileo’s cat. Whether we like it or not, every one of us will ultimately be touched by sequence data and the acid test will be its usefulness, or lack thereof, in specific clinical settings.

    While only a handful of sequenced human genomes were available a few years ago, by the end of 2011 American and European laboratories will likely finish sequencing 9,000 and 6,000 human genomes, respectively. In contrast, the Beijing Genomics Institute (BGI) in Shenzhen will complete somewhere between 10,000 and 20,000 genomes on its own.

    Merck has signed a statement of intent to collaborate with BGI Shenzhen to explore opportunities in the healthcare space, and Twins UK and BGI Shenzhen will collaborate to sequence the methylomes of 5,000 twins to discover therapeutic targets. The U.K. government is set to examine whether an entire healthcare system is ready for genetic testing in the cancer sphere, with the National Health Service to begin mutation testing on as many as 12,000 cancer patients by 2011.

    While this testing is with a very limited number of genes, it is inevitable that, as costs fall, whole-genome sequencing will become a reality throughout entire populations, and pharmaceutical and data-analysis companies will be major participants.

    A proactive clinical approach to the sequencing deluge has already started at the Beth Israel Deaconess Medical Center, where clinicians, researchers, mathematicians, and software companies are creating and integrating new tools for sequence analysis and the training of next-generation molecular pathologists. While sophisticated noninvasive imaging technologies are de rigueur, it is molecular pathology enhanced by high-performance computing that will be the gateway to clinically actionable information from sequencing data.

  • Clinical Challenges

    Whole-genome sequencing has revealed the causative single-gene products altered in Miller syndrome and a form of Charcot-Marie-Tooth neuropathy in specific families. Some healthy couples can now determine whether they, their parents, or grandparents are carriers of highly penetrant and high expressivity variants that may manifest as a particular trait in their children. These examples illustrate a clinical reality; knowing about a condition, but being unable to treat it, can have long-lasting emotional consequences. Few therapies exist for most of these thousands of Mendelian conditions.

    A more relevant clinical challenge concerns predictions on the future of healthy individuals in whom vascular disease, obesity, and dementia will develop in their lifetimes, where hundreds of gene products—under the epigenetic influences of nurture, diet, drugs, and stress—sculpt unique outcomes over many decades.

    Precisely predicting any future outcome must inevitably involve analysis of methylomes and transcriptomes from clinically relevant samples (e.g., from normal coronary arteries, reproductive tissue, or deep brain regions), but these are unavailable from healthy individuals owing to profound unresolved ethical, legal, and clinical issues involving the healthy patient, the doctor, and the service provider.

    Predictions on quantitative traits underpinned by degenerate networks are the most significant challenge to “bullet-train biotechnology”, and the jury is out on the extent to which there will be significant clinical impact in therapeutic contexts.

    While most human diseases involve cells with diploid genomes, cancer is different. Solid tumors constitute 90% of all cancers, and they are exceedingly heterogeneous at the cellular level. This heterogeneity is apparent from DNA sequencing of solid tumors and their metastases, every one of which is unique in terms of its combination of variants and structural alterations. It is sobering that the billion-dollar blockbuster drug Herceptin, which is the poster child of breast cancer treatment, is not targeted to a mutation but to amplification of the normal Her2 gene product via segmental aneuploidy.

    Personalized oncology is really personalized group treatment. In this group context, some variants in the KRAS, BRAF, and EGFR genes appear promising as patient stratifiers, but only Phase III clinical trials will determine their true clinical value.

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