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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

  • Unrealistic Expectations

    In the area of mental illness, three Nobel laureates (James Watson, Eric Kandel, and Sydney Brenner) and colleagues surprisingly advocate the sequencing of 100,000 genomes from individuals with schizophrenia, autism, bipolar disorder, and depression as well as the use of mouse models to devise new treatment strategies for mentally ill patients. They further propose to “reset” schizophrenic and autistic brains on the basis of rodent data.

    The ethical implications of attempting to reset an anatomically miswired human brain in childhood or adult life is clinically and legally hazardous. Each human brain is anatomically and functionally unique, as evidenced by the enormous variation in symptoms among schizophrenic individuals including different hallucinations, delusions, and dysfunctions in the formulation of thoughts and their expression in language.

    Postmortem data from schizophrenic and autistic individuals reveals neuronal loss in different brain regions in different individuals, such as the subnuclei of the medial dorsal nucleus, cingulate cortex, hippocampal formation, entorhinal cortex, and parahippocampal gyrus. In addition, even if experimental animals experience hallucinations and delusions, they cannot report on such conditions.

    Thus, introducing hundreds of mutated genes individually into mice where different strains have greatly divergent expression of well-known pharmaceutical drug targets in their brains and determining which of those perturbations are causal, which are innocent bystanders, and which are relevant to perturbations in the human brain, is the “ultimate endless staircase”—particularly since existing human data on these conditions reveal that it is large copy-number variants rather than single mutations that play a predominant role. It seems that when your only tool is a hammer, every problem looks like a nail.

    In summary, multilevel data analysis from identical twins, discordant for quantitative traits, provides an excellent platform for testing clinical utility. Second, predictions on the outputs of variants in gene products that are involved in drug metabolism must be rigorously tested in clinical contexts. Third, only Phase III oncology trials, based on median overall survival, will reveal whether the stratification of cancer patients, based on particular variants in their tumors, will be of therapeutic utility.

    Finally, healthy couples will certainly benefit from their personal sequencing information prior to starting a family. However it will be by diagnosing and filtering potentially devastating conditions, via in vitro fertilization as well as preimplantation transcriptome and genome sequencing and associated technologies, that bullet-train biotechnology will contribute significantly to preventive personalized medicine.

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