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Examining molecular biology in humans
 
Alex Parker1, Ian McCaffery2, and Scott D. Patterson2
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The advances in molecular biology discussed above would provide an unprecedented understanding of important disease processes at the cellular level. As described, they would require specific probes targeting, for example, genomic alterations or transcripts of key genes, to allow interrogation of the specific cell types that drive a given disease process. In the coming decades, we hope that tools of this kind could then be adapted to enable in vivo interrogation of an even broader range of analytes in humans—rather than in resected tissue—in a relatively non-invasive and non-destructive manner. It is reasonable to expect to gain an increased understanding of disease states and treatment response by examining a range of molecules and molecular processes in human tissues in real time. The ability to interrogate human physiology in vivo is currently rather limited. While the resolution of different imaging techniques is improving and the methods that can be employed in humans are expanding—for example, MRI for soft tissue imaging in tissue remodeling (13)—most available methods query physiological or morphological changes at the level of tissues or organs, which is far different from the scale of individual cells or molecules. Advances have been made in the detection of tumor cells using radiolabeled antibodies that bind specifically to tumor cells [e.g., in the development and monitoring of Rituxan therapy in lymphoma (14)] as well as in the detection of cell proliferation using PET imaging (15). Although the use of tagged antibodies to image tissues is developing quickly, these technologies are non-multiplexable and restricted by the current relatively low resolution of PET imaging technology. Recent advances that may herald a change in this area include optical imaging of antibody-bound molecules (16) or specific enzymatic activities (17) in small animals, bringing the level of specificity to single molecular species, if not yet at a molecular scale.

Imagine the power of being able to interrogate cancer patients for a range of specific somatic mutations in real time, while simultaneously tracking the phosphorylation state of key cellular second messengers (ERK, STATs, AKT, etc.) within in situ tumor tissue during the course of therapy. A researcher could answer the question of tumor heterogeneity within an individual, as well as follow what happens in response to therapy over time. Once achieved, this could no doubt be applied to other pathophysiologies. Such tools could potentially also represent superior early detection diagnostics, enabling interventions earlier in the disease processes before symptoms representing pathogenic processes become manifest.

By making it possible to interrogate multiple different analytes simultaneously within humans in real time, the future technologies we envision here could enable the next generation of clinical scientists to build on and synthesize all of the knowledge gained from in vitro and in vivo animal studies to achieve a truly deeper and more integrative understanding of human physiology. Before this novel synthesis can be achieved, however, one additional challenge must be met—the informatic challenge. Although new computational approaches are being developed to store and analyze the massive n-dimensional data sets that current technologies routinely generate, the increases in size and complexity of such data will only accelerate as new technologies come online. Seeing is still believing and humans can probably best conceptualize what is going on at the organismal level if the molecules and pathways of interest can be visualized—that is, development of the means to turn massively complex data matrices into representations that can be understood and acted on by humans will be one of the key challenges of the next three decades. Although this was an exercise in what we would like to see in a few decades, the wishes expressed in this article don't seem that far fetched given the pace of molecular analytic technology development.

Acknowledgments

The authors declare no competing interests.

Correspondence
Address correspondence to Scott Paterson, Molecular Sciences, Amgen, Inc., One Amgen Center Drive, MS 38-3-A, Thousand Oaks, CA 91320, USA. Email: [email protected]

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