Back to the future: molecular biology meets metabolism.

As biological scientists we aspire to understand how organisms, organs and cells work. Whenever it is possible to hone things down in a reductionist manner to a single metabolite, protein, RNA, or gene, the chances for simplicity and clarity are enhanced. This “reductionist” approach has been wildly successful over the past halfcentury, and there is no reason to cast doubt on its future utility. In contrast, all of us know that molecules do not operate in isolation, and that the robustness of life can be attributed to the web of interactions formed among the substances from which we are made. The orchestration of this web holds the keys to our ultimate understanding of biology. The 76th Annual Cold Spring Harbor Symposium on Quantitative Biology brought together two groups of scientists that seldom self-attract, molecular biologists and physiologists. I saw this event as confirmation that we now recognize that the webs we are seeking to connect and understand will be composed equally of chemicals (metabolites) and polymers (proteins, RNAs and genes). Historically, the field of physiology—as prosecuted with focus on nutrient metabolism—formed a cornerstone for the foundation of modern genetics and the successful reductionism of molecular biology. The single largest leap forward in the field of post-Mendelian genetics came from the studies of Archibald Garrod, who deduced the relationship between gene and enzyme in his seminal studies of inborn errors of metabolism (Garrod 1923). By decades the work of Garrod preceded the seminal, one gene:one enzyme, discoveries of Beadle and Tatum (1941). It is notable that the latter science also focused on metabolism—more specifically, the pathways used by Neurospora crassa to synthesize amino acids. Some 20 years later, Jacob and Monod conceptualized the operon theory of bacterial gene expression, wherein promoters, operators and repressors were presciently hypothesized (Jacob and Monod 1961). It was the ability of Escherichia coli to induce catabolism of lactose as an alternative carbon source to glucose that framed the classical studies illuminating the essence of bacterial gene regulation. The field of molecular biology began its dominance some four decades ago, and has continued to prosecute science at the interface of metabolism and genetics. So powerful were the techniques, however, that molecular biologists were no longer tied to the metabolic pathways to which they were historically linked. Indeed, one needed to know essentially nothing about metabolism to clone any gene one wanted. Pull-down and yeast two-hybrid experiments can treat metabolism as if it were no more important than tris-(hydroxymethyl)-aminomethane (Tris) buffer. Gene knockouts, in situ hybridizations, immunohistochemical stainings, DNA microarrays, CHIP:Seq, RNA:Seq, and chromosomome capture assays—none of these approaches need pay any mind to the fact that the regulatory state of a cell, organ, or organism must be integrally intertwined with metabolic state. Yes, it is generally appreciated by molecular biologists that the regulatory state of a cell probably has something to do with its metabolic state. In contrast, only recently have we begun to re-awaken to the fact that the reciprocal of this relationship must also be true.