Biochemistry is the study of the chemistry of living organisms. It includes knowledge of the structure and function of the molecules found in the biological world, and understanding of the precise pathways by which these molecules are synthesized and degraded. In more recent years, with the development of powerful scientific instruments, biochemistry has also come to include the development of ways to synthesize molecules that duplicate those of living systems, and molecules that can perform entirely new functions. FOUNDATIONS The foundations of modern biochemistry were laid in the 18th century by such figures as the British scientist Joseph \TPriestley\t, who discovered oxygen in 170; the French chemist Antoine Laurent \TLavoisier\t, who showed that animals needed oxygen and that respiration involved the oxidation of substances; and the Swedish chemist Carl Wilhelm SCHELE, who isolated citric, lactic, and uric acid from biological sources. Throughout the century that followed Priestley's discovery, however, biochemistry was considered simply as an aspect of other sciences as applied to living organisms. Thus thermodynamics, the study of the relationships of heat to work and energy, was applied to \Tbiology\t by the German scientists Julius Mayer (1814-78) and Hermann \THelmholtz\t. Also, in the hands of the French physiologist Claude \TBernard\t, physiology soon became the study of chemical pathways in the living organism that is, \Tmetabolism\t. The philosophical problem that occupied much of the 19th century, with respect to living organisms, was that of vitalism. At issue was whether organisms have capabilities derived not only from chemical and physical properties but also from an unknown and perhaps unknowable elan vital, or "vital force." The importance of this debate rested on the fact that if the vitalists were correct, biology and biochemistry could go only so far and no farther in scientific exploration. The first important blow against vitalism was struck in 1828 by the German chemist Friedrich \TWohler\t when he synthesized urea, a substance previously known to be made only by living organisms. The vitalis question, however, was not yet settled. In France, Louis \TPasteur\t'S work in the field of bacteriology led him to the conclusion not only that spontaneous generation--the generation of life from nonliving matter--was impossible, but also that all biological functions, such as fermentation, depended on the presence of living organisms. This was still a form of vitalism, although on a much higher scientific level than the older, naive speculations. Pasteur was opposed in his view by the German chemist Justus von \TLiebig\t, but the issue was not settled until 1897, when another chemist, Eduard \TBuchner\t, showed clearly that glucose could be fermented by a nonliving process in the laboratory. During the first third of the 20th century, the burgeoning of \Torganic chemistry\t put biochemistry on a sound scientific footing. Hundreds of hitherto unknown materials were now being determined. Preeminent in this field was the work of the German biochemist Emil \TFischer\t and his students, along with the investigations of the German biologist Peter Michaelis (1900-) and any others into the dynamics of \Tenzyme\t action. Not until the American biochemist James B. \TSumner\t crystallized the enzyme urease in 1926, however, and showed that it and, by inference, all enzymes are simply \Tproteins\t, was the last vestige of vitalism laid to rest. MAJOR DEVELOPMENTS A new era in biochemistry began with the introduction of the use of \Lisotope\ls by German Rudolf Schoenheimer (1898-1941) and the American David Reittenberg (1906-). Scientists could now follow individual substances in living tissues by tagging one or more of their atoms or molecules and following them as they were incorporated into larger molecules, modified, broken down into simpler molecules, and finally excreted. Through the use of isotopes, most of the major pathways of metabolism have since been revealed, including the biochemical cycles--self-renewing reaction sequences in which the last product formed becomes part of the first reaction in the sequence. This concept first appeared in 1933, when the German-English scientist Sir Hans Adolf \TKrebs\t and coworkers proposed the urea cycle. Many biochemical cycles have since been determined; perhaps the most famous is the tricarboxylic acid cycle (see \TKrebs cycle\t). Protein Structure Other advances in technology enabled scientists to make similar critical discoveries that are central to biochemical knowledge today. Proteins, for example, are of basic importance to biochemists because they are essential to the structure and function of all living organisms. In the early 20th century, Fischer and his colleagues had already shown that proteins are polymers of \Lamino acid\ls linked together in a linear manner by \Tpeptide\t bonds. Following Sumner's proof that enzymes are proteins, biochemists began to try to unravel the structure of these molecules in order to synthesize them. This was facilitated in 1941 by the development of partition \Tchromatography\t, a method of separating similar molecules by moving a mixture of them over a long column or strip of material that absorbs the molecules at different rates. The amino acids in a milk protein were established in this way in 1949, and in 1953 the English biochemist Frederick \TSanger\t was able to determine the structure of the protein \Tinsulin\t. Automated instruments can now determine the amino acids and their order in giant proteins within a matter of hours. The activity of proteins was found to be determined not only by their composition but also by their three-dimensional configuration, and in the early 1950s the American chemist Linus \TPauling\t showed that proteins have a basically helical structure. This knowledge provided the groundwork for understanding, in chemical and molecular terms, how enzymes work--a matter of crucial importance, because enzymes direct the synthesis of all the other components of biological organisms. The overriding question then became: what mechanism, in turn, determines the structure of these crucial proteins? Whatever the mechanism, it would be the one that enables life forms to pass on their characteristics from generation to generation. Protein Synthesis In 1944 the Canadian-American bacteriologist Oswald T. \TAvery\t and coworkers had already shown that the \Tnucleic acid\t called \TDNA\t was the material in the \Tcell\t that is responsible for inducing heritable changes in almost all living organisms, and that it is contained in chromosomes. In 1952, American scientist Paul Zamecnik further showed that proteins are synthesized on ribosomes, which are cellular structures made of protein and another nucleic acid called \TRNA\t. Shortly thereafter, Zamecnik and another American, Mahlon Hoagland, found that another form of \TRNA\t activates amino acids so that hey can be polymerized into proteins on the ribosomes. the race was now on to tie this information together, and the key to the problem was to find how genetic information is stored on the \TDNA\t molecule. This key was provided in 1953 by the joint efforts of the American biologist James D. \TWatson\t and the English biochemist Francis \TCrick\t. Basing their work on X-ray data provided by Maurice \TWilkins\t and Rosalind \TFranklin\t, as well as Publishing's research, they showed that the \TDNA\t molecule is a double helix in which each single helix is the complement of the other. \TDNA\t was found to direct the synthesis of \TRNA\t copies, which translocate to the ribosomes. There, given a supply of activated amino acids, \TRNA\t governs the production of proteins--including the enzymes that synthesize the other cellular components. Thus all the information needed to build a biological organism is ultimately found in the \TDNA\t molecule. Determination of the form in which this information is stored--the \Tgenetic code\t--has been a major achievement of biochemical research. Rapid methods now exist of the synthesis of proteins from amino acids. Biological Membranes The development of radioactively labeled high-potency antibodies to many proteins has enabled biochemists to detect, with some accuracy, amounts of cellular constituents measuring no more than billionths of a gram. Such techniques are needed to explore the complex chemistry of cell membranes (see \Tmembrane chemistry\t). These highly reactive structures are engaged in actively moving materials in and out of the areas they enclose, conducting messages, and performing vital functions that provide energy to the organism and protect it against drugs and toxins. The study of cell membranes is one of the major fields of current biochemical research. THE BIOCHEMISTRY OF DISEASE Another major field of study is the biochemistry of disease. Early in the 20th century, certain inherited illnesses had already been defined as inborn errors of metabolism. (In more modern terms, they are diseases involving defective enzymes.) In the 1940s, American geneticists George W. \TBeadle\t and Edward L. \TTatum\t then postulated that each gene in a chromosome codes for one particular enzyme, and that the relative amounts and activities of the enzymes determine all other heritable characteristics of an organism. This postulate remains a cornerstone of modern biochemical thinking although it has since been restated in a much more complex manner. Illnesses are known in which a change in a single molecule, in the \TDNA\t of one chromosome, results in the substitution of a single amino acid out of many hundreds in a protein, leading in turn to a life-threatening malfunction in the affected individual. Immunology Research in the 1960s and 1970s has also provided a solid chemical basis for work in \Timmunology\t. The mammalian organism fends off disease by means of two major mechanisms. One is the deployment of special cells--the leukocytes and macrophages (see \Tblood\t)--to ingest invading organisms. The other is the production of antibodies (see \Tantibody\t) that can attach to the invader and destroy it, in association with a group of proteins in the blood. Biochemists, in careful studies of antibody structure, have found invariant and variable regions of these proteins. The invariant regions determine the biological properties of the antibody, and the variable ones determine with which \Tantigen\t the antibody will combine. Future advances in medicine will depend in great part on further knowledge of the chemistry of antibodies and related compounds. Hormones Also of great importance is the biochemical study of \Lhormone\ls. Endocrine hormones are chemicals secreted into the bloodstream by glands; carried to their target cells, they can drastically influence the metabolism of those cells. In general, a gland secretes a hormone in response to a stimulus from elsewhere. For example, nerve processes leading to the portion of the brain called the hypothalamus secrete \Lneurotransmitter\ls (chemicals related to the amino acids) that cause the hypothalamus, in turn, to secrete one of several so-called releasing hormones. These hormones travel directly to the anterior pituitary gland and cause the release of other hormones called trophic hormones. The latter then travel to appropriate glands where they can combine with receptors for a particular hormone. (Many of these receptors are on the outer membrane of the cell and show strong chemical relationships to antibody structure.) Such hormone-receptor combinations enter the cell and initiate metabolic changes that are under active investigation in many laboratories. From the foregoing it is evident that an "endocrine" disease can be due to defects at many levels, from the interaction of nervous tissue with the hypothalamus to abnormal responses deep within the cell. Such defects are known clinically, and in many cases the biochemical defects are now also known. Cancer Research One of the leading areas of biochemical research in medicine is that of \TCancer\t. Contemporary research indicates that many and perhaps all cancers result from chemical changes in the nucleic acids. Many cancer-producing chemicals do so by adding or subtracting portions of individual bases in the \TDNA\t molecule. Of great interest today are the areas of \TDNA\t called proto-oncogens (from Greek words meaning "antecedent tumor genes"). Many of these areas are thought to play a role in activating normal growth hormones. In laboratory studies, animal proto-oncogenes have been broken off from their chromosome, altered somewhat chemically, and introduced into certain viruses called \Lretrovirus\les. The resulting molecules, called \Loncogene\ls, are responsible for cancer production by one class of viruses; biochemistry made it possible to understand the mechanism of this process. Genetic Engineering Perhaps the most dramatic development arising from advances in biochemical research has been that of \Tgenetic engineering\t. Using techniques that capitalize on current knowledge of protein and nucleic-acid metabolism and on advances in endocrinology, microbiology, and many other biological sciences, researchers can now introduce synthetic strands of \TDNA\t into bacteria and cause them to produce large amounts of specifically desired proteins. For example, human insulin and \Tinterferon\t are now made in quantity in this manner, and a host of other biochemicals are in the process of similar synthesis-including modified proteins never before known. Thus biochemistry, while increasingly important in modern society as a separate field of research, is also blending more and more with other biological disciplines. The growth of such new areas of study as cell biology and molecular biology reflects this integration. Increasingly, current problems in the biological sciences are being solved by team efforts of scientists from many disciplines who have mastered their once-separate fields. \TAaron\t D. FREEDMAN, M. D. Bibliography: Briggs, T., and Chandler, A. M., eds., Biochemistry (1987); Hill, H. W., and Feigl, D. M., Chemistry and Life, 3d ed. (1987); Wilson, Keith, and Goulding, K. H., A Biologist's Guide to Principles and Techniques of Practical Biochemistry, 3d ed. (1986).