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Decoding the Molecular Universe - Workshop Report
Citation:
Metz, T., J. Adkins, P. Armentrout, P. Chain, F. Chu, C. Corley, J. Cort, E. Denis, D. Drell, K. Duncan, R. Ewing, F. Fernandez, O. Fiehn, N. Garg, S. Grimme, C. Henry, R. Hettich, T. Kind, R. Linington, T. Northen, K. Overdahl, A. Patrinos, D. Raftery, P. Rigor, R. Smith, J. Sobus, J. Teeguarden, A. Vertes, K. Waters, B. Webb-Robertson, A. Williams, AND D. Wishart. Decoding the Molecular Universe - Workshop Report. Pacific Northwest National Laboratory, Richland, WA, 2023. https://doi.org/10.48550/arXiv.2311.11437
Impact/Purpose:
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Description:
In the mid-1980s, several events occurred that led to the conceptualization and eventual initiation of the world’s largest collaborative biological project – the Human Genome Project (HGP). In 1985, Robert Sinsheimer – then Chancellor of the University of California, Santa Cruz – convened a workshop with 18 participants to discuss the feasibility of sequencing the human genome, and then wrote and distributed a workshop summary.1 Also in 1985, Charles DeLisi, who had just left a senior investigator position at the NIH to become the director of the Health and Environmental Research Programs at the U.S. Department of Energy, asked Mark Bitensky of Los Alamos National Laboratory to organize a workshop to discuss the same topic, which took place March 3-4, 1986 in Santa Fe.2 Later that year, Renato Dulbecco published a perspective in the journal Science on the knowledge that a fully sequenced human genome would provide in the fight against cancer.3 Other similar events followed, and extensive efforts occurred behind the scenes – all of which culminated in a $13-million line item in President Ronald Reagan’s 1987 budget request that was realized in 1988 as the first official funding of the HGP. After 13 years and $3 billion, the HGP resulted in a 90% completion of the human genome sequence and innumerable increases in understanding of the roles of genes in human biology and environmental systems (e.g., soil microbial communities), key advancements in gene and transcript sequencing capabilities, and substantial beneficial economic impacts.4 Yet an individual’s genetics alone has been shown to explain just 40% of disease,5 with environmental exposures6 (e.g., via chemicals) and interactions of such with the genome assumed to explain the remainder.7In contrast, the single most-focused U.S. effort to date towards establishing capabilities that would enable complete knowledge of the role of small molecules – defined as non-protein, non- polymer molecules less than ~1500 Daltons – in biological systems was the NIH Common Fund Metabolomics Program, a 10-year (2013-2023) and ~$200-million effort focused on establishing a national capacity in and advanced capabilities for metabolomics in biomedical applications and which was roughly 6.7% of the investment made towards sequencing the human genome. Many groundbreaking and significant resources (e.g., the National Metabolomics Data Repository - the Metabolomics Workbench8) and technological advancements were made and new biological understanding achieved under that program, particularly in the understanding of the role of metabolism and metabolites in cancer.9-14 However, the scientific community is still unable to ascertain the complete chemical composition and quantities of small molecules in any given sample, which is one of the last remaining steps towards achieving a complete and foundational understanding of biological and environmental systems. This is likely because the fundamental analytical paradigms implemented in high throughput measurements of small molecules (e.g., ‘metabolomics’) have not changed in over 50 years. The first attempts to perform modern high throughput analysis of small molecules in biological systems were made by Linus Pauling and Arthur Robinson in the late 1960s and early 1970s in support of Pauling’s concept of ‘orthomolecular medicine.15,16 Pauling and Robinson utilized chromatography coupled with flame ionization detection and then mass spectrometry to detect and quantify the small molecule components of biofluids such as urine, and then performed pattern recognition analysis to identify signatures that were correlated to a patient's phenotype. Many significant advancements in measuring small molecules have been made since,17 and such measurements are now performed with orders of magnitude higher throughput, higher quality (e.g., in terms of accuracy and precision), and more molecules routinely measured...
URLs/Downloads:
DOI: Decoding the Molecular Universe - Workshop Report
FINAL REPORT.PDF (PDF, NA pp, 6430.35 KB, about PDF)
https://arxiv.org/abs/2311.11437