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Cover  DNA from Drosophila embryo nuclei were exposed in situ to an interstrand DNA crosslinking agent. The DNA was then deproteinized and spread under fully denaturing conditions. The micrograph (left) and contour map (right) reveal periodic "bubbled" regions, where proteins in the native chromatin blocked access of the crosslinker to the DNA, interspersed with nondenatured regions where the crosslinking agent gained entry to the double helix (Hanson, C.V., Shen, C.-K.J., and Hearst, J.E. [1976]. Crosslinking of DNA in situ as a probe for chromatin structure. Science 193, 62-64). This experiment elegantly capped the breathtaking 30-month period during which the nucleosome structure of chromatin was discovered. First intimated by the regularly spaced pattern by which DNA in rat liver nuclei is cut by an endogenous nuclease (Hewish, D.R., and Burgoyne, L.A. [1973]. Chromatin substructure. The digestion of chromatin DNA at regularly spaced sites by a nuclear deoxyribonuclease. Biochem. Biophys. Res. Commun. 52, 504-510), nucleosomes were convincingly observed 8 months later (Olins, A.L., and Olins, D.E. [1974]. Spheroid chromatin units (v bodies). Science 183, 330-331). Soon thereafter, Roger Kornberg and Jean Thomas defined the histone protein-protein pairing associations that constitute the nucleosome [Kornberg, R.D., and Thomas, J.O. [1974]. Chromatin structure; oligomers of the histones. Science 184: 865-868; Kornberg, R.D. [1974]. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868-871). Thus, the discovery of the nucleosome was an example of convergent science, in which three approaches came together contemporaneously. The first two approaches were electron microscopy of spread chromatin (Olins and Olins, op. cit.) and biochemical studies on purified histones and extracted chromatin (Kornberg and Thomas. op. cit.). The third approach (Hanson, Shen, and Hearst, op. cit.) was a prescient antecedent to the field we today call chemical biology, in which small molecules are applied to report on biology in native systems. The probe ingeniously employed by Hearst and colleagues was a relative of a family of natural products, psoralens, derived from plants of the umbelliferae family (e.g., celery, parsnips) and was used by ancient Hindu physicians to photodynamically treat (with sunlight) hyperplastic skin diseases. Psoralens were plausibly reasoned, 2000 years later, to permeate into cell nuclei. Interstrand crosslinking of DNA by psoralen compounds was reported in 1971. It only remained for a creative laboratory to put everything together and show us nucleosomes in native cell nuclei, as Hearst and colleagues did so ingeniously and convincingly. The figure is reproduced from Science, 1976, 193, 62-64, with copyright permission.Thoru Pederson