Secondary Metabolites in Plants

Secondary metabolites are chemicals produced by plants for which no role has yet been found in growth, photosynthesis, reproduction, or other "primary" functions. These chemicals are extremely diverse; many thousands have been identified in several major classes. Each plant family, genus, and species produces a characteristic mix of these chemicals, and they can sometimes be used as taxonomic characters in classifying plants. Humans use some of these compounds as medicines, flavorings, or recreational drugs.

Secondary metabolites can be classified on the basis of chemical structure (for example, having rings, containing a sugar), composition (containing nitrogen or not), their solubility in various solvents, or the pathway by which they are synthesized (e.g., phenylpropanoid, which produces tannins). A simple classification includes three main groups: the terpenes (made from mevalonic acid, composed almost entirely of carbon and hydrogen), phenolics (made from simple sugars, containing benzene rings, hydrogen, and oxygen), and nitrogen-containing compounds (extremely diverse, may also contain sulfur).

The apparent lack of primary function in the plant, combined with the observation that many secondary metabolites have specific negative impacts on other organisms such as herbivores and pathogens , leads to the hypothesis that they have evolved because of their protective value. Many secondary metabolites are toxic or repellant to herbivores and microbes and help defend plants producing them. Production increases when a plant is attacked by herbivores or pathogens. Some compounds are released into the air when plants are attacked by insects; these compounds attract parasites and predators that kill the herbivores. Recent research is identifying more and more primary roles for these chemicals in plants as signals, antioxidants , and other functions, so "secondary" may not be an accurate description in the future.

Consuming some secondary metabolites can have severe consequences. Alkaloids can block ion channels, inhibit enzymes , or interfere with neurotransmission, producing hallucinations , loss of coordination, convulsions, vomiting, and death. Some phenolics interfere with digestion, slow growth, block enzyme activity and cell division, or just taste awful.

Most herbivores and plant pathogens possess mechanisms that ameliorate the impacts of plant metabolites, leading to evolutionary associations between particular groups of pests and plants. Some herbivores (for example, the monarch butterfly) can store (sequester) plant toxins and gain protection against their enemies. Secondary metabolites may also inhibit the growth of competitor plants (allelopathy). Pigments (such as terpenoid carotenes, phenolics, and flavonoids) color flowers and, together with terpene and phenolic odors, attract pollinators.

Secondary chemicals are important in plant use by humans. Most pharmaceuticals are based on plant chemical structures, and secondary metabolites are widely used for recreation and stimulation (the alkaloids nicotine and cocaine; the terpene cannabinol). The study of such plant use is called ethnopharmacology. Psychoactive plant chemicals are central to some religions, and flavors of secondary compounds shape our food preferences. The characteristic flavors and aroma of cabbage and relatives are caused by

nitrogen-and sulfur-containing chemicals, glucosinolates, which protect these plants from many enemies. The astringency of wine and chocolate derives from tannins. The use of spices and other seasonings developed from their combined uses as preservatives (since they are antibiotic) and flavorings.

see also Flowers; Herbivory and Plant Defenses; Metabolism, Cellular; Poisons

Jack Schultz

Bibliography

Agosta, William. Bombardier Beetles and Fever Trees: A Close-up Look at Chemical Warfare and Signals in Animals and Plants. Reading, MA: Addison-Wesley, 1996.

Bidlack, Wayne R. Phytochemicals as Bioactive Agents. Lancaster, PA: Technomic Publishers, 2000.

Karban, Richard, and Ian T. Baldwin. Induced Responses to Herbivory. Chicago: University of Chicago Press, 1997.

Rosenthal, Gerald A., and May R. Berenbaum. Herbivores, Their Interactions with Secondary Plant Metabolites. San Diego, CA: Academic Press, 1991.

Physiology

Plant physiology encompasses the entire range of chemical reactions carried out by plants. Like other living organisms, plants use deoxyribonucleic acid (DNA) to store genetic information and proteins to carry out cellular functions. Enzymes regulate both anabolism (buildup of complex macromolecules ) and catabolism (the breaking down of macromolecules into simple molecules). Unlike animals, plants create a large variety of secondary metabolites, complex molecules with a range of specialized functions.

Structure and Function of Macromolecules

DNA.

Deoxyribonucleic acid (DNA) is a high-molecular-weight polymer , containing phosphate, four nitrogen bases, and the pentose sugar deoxyri-bose. There are two pyrimidine bases, cytosine and thymine, and two purine bases, adenine and guanine. These nitrogen bases are joined to long chains of alternating sugar and phosphate. The three-dimensional structure of DNA consists of a two-stranded alpha-helix with each strand consisting of a long chain of polynucleotides and the strands joined through the bases by hydrogen bonding. The two strands are precisely complementary in their base sequence, since adenine in one chain is always paired with thymine on the other (and vice versa) and, similarly, guanine is always paired with cytosine (see the accompanying figure of the structure of DNA).

DNA occurs in the chromosomal material of the nucleus, closely associated with proteins called histones. In higher plants, DNA is also present in the chloroplasts and mitochrondria of each cell. The sequence of DNA codes for protein synthesis in such a way that different base triplets determine, in turn, the amino acid sequence of that protein.

RNA.

Ribonucleic acid (RNA) is similar in structure to DNA except that a different sugar, ribose, is present and the thymine of DNA is replaced by uracil. RNA also differs from DNA in being single-rather than double-stranded and it is also more labile (unstable) than DNA. The purpose of RNA is to transfer the genetic information locked up in the DNA so that proteins are produced by the plant cell. In order to carry out this operation, there are three classes of RNA. Messenger RNA (mRNA) provides the exact template on which proteins of specific amino acid sequences are synthesized. Ribosomal RNA provides the site within the cytosol for protein formation. Transfer RNA (tRNA) makes up to 10 to 15 percent of the total cellular RNA, and serves an essential function in the decoding process of translating mRNA sequences into proteins. It carries amino acids to the ribosome, where they are linked together in the sequence dictated by mRNA. The result is a protein.

Proteins.

The proteins in plants, as in other organisms, are high-molecular-weight polymers of amino acids. These amino acids are arranged in a given linear order, and each protein has a specific amino acid sequence. In the simplest cases, a protein may consist of a single chain of amino acids, called a polypeptide. Several identical chains may, however, aggregate by hydrogen bonding to produce complex units with a much higher molecular weight. A polypeptide may coil up partly as an alpha-helix and thus adopt a particular three-dimensional structure. Many proteins are rounded in shape and hence are called globular proteins.

Many proteins are enzymes that catalyze particular steps in either primary or secondary metabolism. There are also many different storage proteins, found mainly in seeds, that provide a source of nitrogen in the young seedling. Perhaps the most important plant protein is ribulose 1,5-bisphos-phate carboxylase, the essential catalyst for photosynthesis, which comprises up to 50 percent of the leaf protein in most green plants. Each green leaf, however, may synthesize up to one thousand different proteins, each with an assigned role in plant growth and development.

Polysaccharides.

The chemistry of polysaccharides is, in a sense, simpler than that of the other plant macromolecules since these polymers contain only a few types of simple sugars in their structures.

The most familiar plant polysaccharides are cellulose and starch. Cellulose represents a very large percentage of the combined carbon in plants and is the most abundant organic compound on Earth. It is the fibrous material of the cell wall and is responsible, with lignin, for the structural rigidity of plants. Cellulose is known chemically as a beta-glucan and consists of long chains of β1 → 4 linked glucose units, the molecular weight varying from 100,000 to 200,000. Cellulose occurs in the plant cell as a crystalline lattice, in which long straight chains of polymer lie side by side linked by hydrogen bonding.

Starch differs from cellulose in having the linkage between the glucose units as α1 → 4 and not β1 → 4 and also in having some branching in the chain. Starch, in fact, comprises two components, amylose and amylopectin. Amylose (approximately 20 percent of the total starch) contains about three hundred glucose units linked in a simple chain, which exists in vivo in the form of an alpha-helix. Amylopectin (approximately 80 percent) contains chains with regular branching of the main chain by secondary α1 → 6 linkages. Its structure is thus randomly branched. Starch is the essential storage form of energy in the plant, and starch granules are frequently located within the chloroplast close to the site of photosynthesis.

The different classes of polysaccharide fall into two groups according to whether they are easily soluble in aqueous solutions or not. Those that are soluble include starch, inulin, pectin, and the various gums and mucilages. The gums that are exuded by plants, sometimes in response to injury or infection, are almost pure polysaccharide. Their function in the plant is not entirely certain, although it may be a protective one. The less-soluble polysaccharides usually comprise the structural cell wall material and occur in close association with lignin. Besides cellulose, there are various hemicelluloses in this fraction. The hemicelluloses have a variety of sugar components and fall into three main types: xylans, glucomannans, and arabinogalactans. They are structurally complex, and other polysaccharide types may also be found with them.

Anabolism and Catabolism: Biosynthesis and Turnover

Anabolism.

Anabolism is the energy-requiring part of metabolism in which simpler substances are used to build more complex ones. In plants, primary metabolites are built up from very basic starting materials, namely CO₂, H₂ O, nitrate (NO^— 3), sulfate (SO₄^2–), phosphate (PO₄^3–), and several trace metals. Each metabolite is formed by a discrete biosynthetic pathway, each step in the pathway being catalyzed by a separate enzyme.

The most important anabolic pathway in green plants is the formation of starch from external CO₂ through the process of photosynthesis. Light energy is used to capture the atmospheric CO₂, taken in via the stomata , and convert it to sugar by condensing it with glycerophosphate, forming glucose 1-phosphate in the Calvin-Benson (C₃) cycle. In tropical plants, an additional carbon pathway is involved in photosynthesis, whereby the CO₂ is first captured by the plant in the form of simple organic acid such as malate. This is known as the Hatch-Slack (C₄) cycle, which provides a more efficient use of atmospheric CO₂. Regardless of the pathway, the glucose 1-phosphate is then used to produce starch. A similar end-product of carbohydrate metabolism is sucrose. Sucrose is important as an easily transportable form of energy within the plant. Starch, by contrast, is laid down mainly in the seed (e.g., of a cereal grain), and is not remobilized until that seed germinates in the following year.

Another equally important anabolic pathway in plants is that leading to protein synthesis. The starting material is usually inorganic nitrate taken in via the root from the soil and transported up the stem into the leaf. Here it is reduced to ammonia, which is immediately combined with alpha-ketoglutaric acid to yield glutamine. By a reshuffling process, glut-amine is then converted to glutamic acid and by a variety of related processes the other eighteen protein amino acids are produced. These are then combined with tRNA and assembled together to yield the polypep-tide chain(s) of protein.

Yet another anabolic mechanism is the formation of a lipid (an oil or fat). Lipids are produced from fatty acids, formed in turn from acetylcoenzyme A, a product of glycolysis. Lignin, the building strength in wood and in plant stems, is produced by a pathway starting from the sugar sedoheptulose, available from the Calvin-Benson cycle. The nucleic acids and their bases are formed from protein amino acids. Purines are produced from glycine while pyrimidines are produced from aspartic acid.

Catabolism.

Catabolism includes any metabolic process involving the breakdown of complex substances into smaller products. Catabolism is thus the reverse of anabolism. No sooner is sugar available to the plant from photosynthesis than it is turned over and metabolized in order to provide the energy (e.g., in the form of adenosine triphosphate [ ATP ]) needed to drive the various processes that are taking place in the cell. Some ATP is provided in the process of glycolysis, by which glucose 1-phosphate is broken down to pyruvate and subsequently to acetyl-coenzyme A. The last stages in sugar metabolism include the entry of acetyl-coenzyme A into the Krebs tricarboxylic acid cycle. This process returns the carbon, originally taken in via photosynthesis, back into the atmosphere as respired CO₂, and each turn of the Krebs cycle provides more ATP for the cell.

A related pathway involving the Krebs cycle is the glyoxylate cycle, a pathway for lipid breakdown. This catabolic pathway can also become anabolic, converting the stored lipid into sugar.

In summary, every metabolite in the plant cell is subject to both anabolism and catabolism. In other words, there is a continual turnover, with the building up and breakdown of larger molecules. In general, anabolism involves the input of energy to build molecules, while catabolism involves the release of that energy when molecules are broken down. Thus, the plant is in a continual state of flux or metabolic activity throughout its life cycle.

Primary Metabolites vs. Secondary Metabolites

The compounds present in plants are conveniently divided into two major groups: primary and secondary metabolites. Primary metabolites are those produced by and involved in primary metabolic pathways such as respiration and photosynthesis. Secondary metabolites are clearly derived by biosynthesis from primary metabolites and are generally much more variable in their distribution patterns within the plant kingdom.

Primary metabolites include the components of processes such as glycolysis, the Calvin-Benson cycle, and the Krebs cycle. Primary metabolites are virtually identical throughout the plant kingdom: they are mainly sugars, amino acids, and organic acids. As intermediates in metabolic pathways, these molecules may be present in some activated form. Glucose, for example, when taking part in metabolism, occurs in an energy-rich form as glucose 1-phosphate or as uridine diphosphoglucose. Other primary metabolites are the proteins, nucleic acids, and polysaccharides of plant cells. These have universal functions as enzymes, structural elements, storage forms of energy, and hereditary materials.

Secondary metabolites are produced by biosynthetic pathways, beginning with primary metabolites as starting materials. It has been estimated that about one hundred thousand secondary metabolites have been characterized in plants, and additional substances are continually being discovered. The amount of any secondary compound present in a plant is the result of an equilibrium between synthesis, storage, and metabolic turnover. Regulation of secondary metabolism is complex, and production may be limited to certain organs of the plant and may only take place during a single phase of the life cycle (e.g., during flowering or fruit formation).

Secondary metabolites are conveniently divided into three main chemical classes: the phenolics, the terpenoids, and the nitrogen-containing substances. The phenolics include the lignins, which are the aromatic materials of cell walls, and the anthocyanins, the colorful red to blue pigments of angiosperm flowers. Another phenolic class are the plant tannins , mainly present in woody plants, which have the special property of being able to bind to protein. They impart an astringent taste to plant tissues containing them and are significant flavor components in tea, wine, and other plant beverages.

The terpenoids are probably the most numerous of secondary substances. They are subdivided into monoterpenoids and sesquiterpenoids (essential oils); diterpenoids, including resin acids; triterpenoids (phytosterols, cardenolides, limonoids, etc.); and tetraterpenoids (carotenoids ). The most visible terpenoids are the yellow to red carotenoid pigments present in flowers and fruits. Limonin gives lemon its characteristic taste. By contrast, volatile terpenoids give caraway and carrot their characteristic scents.

The nitrogen-based secondary metabolites are variously classified as amines, alkaloids, cyanogenic glycosides, and mustard oil glycosides. In general they have only limited occurrences. Alkaloids are the best known compounds of this type and are found in 20 percent of all plant families. Some alkaloids, such as morphine, because of their physiological activities in humans, have been used extensively in medicine. Other alkaloids, such as coniine from the hemlock, have been used as poisoning agents.

While the role of primary metabolites is clear, the functions of secondary substances are still uncertain. The anthocyanin and carotenoid pigments, together with the floral essential oils, are necessary to attract animals to flowers. The gibberellins, auxins , and cytokinins, together with abscisic acid and ethylene, control plant growth and development. Alkaloids and tannins deter animals from feeding on green tissues and thus are valuable to plants for limiting the extent of insect herbivory and animal grazing.

see also Alkaloids; Cacao; Carbohydrates; Carotenoids; Cellulose; Coca; Defenses, Chemical; Flavonoids; Lipids; Opium Poppy; Photosynthesis, Carbon Fixation and; Photosynthesis, Light Reactions and; Physiologist; Psychoactive Plants; Terpenes.

Jeffrey B. Harborne

Bibliography

Dennis, D. T., and D. H. Turpin. Plant Physiology, Biochemistry and Molecular Biology. Harlow, Essex, UK: Longman Group, 1990.

Salisbury, F. B., and C. W. Ross. Plant Physiology, 3rd ed. Belmont, CA: Wadsworth Publishing, 1985.

Taiz L., and E. Zeiger. Plant Physiology, 2nd ed. Sunderland, MA: Sinauer Associates,1998.

physiology is defined by dictionaries as ‘the science of the normal functions and phenomena of living things’. The physiology of animals emerged in Europe out of the Renaissance nterest in the experimental method, as exemplified by the work of William Harvey (doctor to Charles I). Harvey's book of 1628 on the Motion of the Heart, ‘Exercitationes Anatomicae de Motu Cordis’, brilliantly analyses structural and functional observations (quantitative as well as qualitative), which remorselessly led him, and similarly lead the present day reader, to the conclusion that the blood circulates, in man as well as in other animals. This volume remains central to our current understanding of the word ‘physiology’ because of its emphasis on experiment, data analysis, and hypothesis testing. Harvey's work also exemplifies the natural symbiois between physiology (‘function’) and anatomy (‘structure’), a science from which physiology was to emerge as a separate discipline in the second half of the nineteenth century. Harvey's book also connects physiology to medicine. Understanding of every disease follows from combining knowledge of the relevant normal physiology to the way in which it is perturbed in the particular disorder (‘pathophysiology’).

Historically, the subsequent meaning of ‘physiology’ is well illustrated by the way in which the word is used in the two following quotations. The first is from 1704 ( J. Harris, Lexicon Technica): ‘Physiology, is by some also accounted a Part of Physick’ (i.e. Medicine), ‘that teaches the Constitution of the Body so far as it is sound, or in its Natural State; and endeavours to find Reasons for its Functions and Operations, by the Help of Anatomy and Natural Philosophy’. The second (a definition of Charles Darwin's colleague T. H. Huxley), 150 years later, is virtually identical to current usage: ‘whereas that part of biological science which deals with form and structure is called Morphology; that which concerns itself with function is Physiology’.

It was the experimental work of Claude Bernard in France in the mid nineteenth century that led to the profound insight that homeostasis is central ot the success and survival of any organism. This implies that physiological systems must necessarily function in such a way as to regulate their internal environment, by means of what we now call ‘feedback’. A homeostatic mechanism requires, at a minimum, a set of sensors to measure the relevant variable (e.g. body temperature), feeding back ‘error signals’ to an integrator (the brain), which controls an effector mechanism to adjust that variable (sweating, shivering, etc.). Such a negative feedback control system will act to return the variable towards the non-perturbed state. Such ideas of control and order are central to understanding and defining the discipline of physiology, whether it be in microorganisms, plants or animals.

The significance of physiology as the key science underpinning health and disease (human and veterinary) accounts for the nomenclature adoped in 1900 by the Nobel Foundation. To recognize key developments in this field, the relevant Nobel Prize is still awarded in ‘Physiology or Medicine’, although many Nobel prize-winners in this category (working in such fields as immunology, molecular biology and bioengineering) would not readily have identified themselves as physiologists. But many would have done so. For example: in cardiovascular physiology, Krogh (for his studies of capillary function), Einthoven (who described the electrocardiogram) and Forssman (who developed cardiac catheterization); in neurophysiology, Sherrington (who conceived the idea of synapses), Adrian (responsible for our original understanding of coding of information by patterns of nerve impulses), and Hubel and Weisel (who worked out how the visual areas of the cerebral cortex analyse specific features of the image); in endocrinology, Banting (insulin) and Guillemin and Schally (identification of the hypothalamic peptides that control the pituitary gland).

The interface between physiology and chemistry led directly to the emergence, in the first half of the twentieth century, of the major new discipline of biochemistry. Hence, such Nobel laureates in ‘Physiology or Medicine’ as Warburg (respiratory enzymes), Krebs (metabolic integration), Brown and Goldstein (cholesterol) and Sutherland (cyclic AMP) would probably not have thought of their scientific research as being part of ‘physiology’.

Another science that grew out of physiology concerns nutrition; yet another is pharmacology, whose foundations arose from the experiemental studies of physiologists such as Loewi (the discoverer of the transmitter substance acetylcholine) and Dale (chemical transmission between nerve cells). Despite the natural and deepening methodological and cultural divergence, over time, of both biochemistry and pharmacology from physiology, they all share the goal of explaining the functions of the body. Moreover, now that the concepts of genetics and the power of molecular biology pervade the whole of biology, the communality of physiology, pharmacology and biochemistry has re-emerged. This is well illustrated by the recent discovery of Furchgott (another Nobel prize winner) and others, that nitric oxide, a tiny gaseous molecule, can convey information between cells simply by diffusing through their membranes.

Harder to define, yet critical to the discipline of physiology, is the term ‘general physiology’. This subject emerged originally from the convergence of nineteenth-century physical chemistry with experimental biology. It was founded on quantitative studies of plant and animal cells. Because of its reductionist goal, general physiology was an obvious forerunner of what is now described as cell and molecular physiology. However, more than this, it attempted to use the theoretical insights gained from the ‘hard sciences’ (physics and chemistry) to provide a rational basis for analyzing living matter, and was thus eager to embrace and test theory quantitatively. An outstanding example of the success of this approach is the experimental analysis of the resting potential and the action potential (nerve impulse) by Hodgkin and colleagues in the late 1940s. Indeed, successful analysis of ‘bioelectricity’ is one of the factors that led to the foundation by physiologists of yet another off-shoot — biophysics. Although there are still (notably in North America) a number of distinguished university departments of Biophysics, growth of this subject as an independent discipline has been hampered somewhat by its failure to meld its ‘physiological’ roots with its links to biological physics (especially X-ray crystallography). However, the work of Nobel laureates Neher and Sakmann provides a spectacular example of how electrophysiological analysis can give biophysical insight not available through other means. These scientists, through clever technical developments, were able to design experiments that allowed structural, and hence functional, changes in single protein molecules (membrane ion channels) to be followed in real time by recording the flow of ionic current through them. By tightly sealing a fine, fluid-filled capillary tube to an extremely small part of a cell membrane, and linking it to a sophisticated amplifier (‘patch clamping’), they were able to measure the current through individual channels, flicking quickly from closed to open states. This physiological insight has very recently been matched by structural studies by MacKinnon and colleagues on membrane channels at atomic resolution.

Physiology has a complex, deep relationship with the approach of reductive science. This is in part because ‘function’, particularly ‘interesting’ or unexpected function, emerges from interactions that can be found only in relatively complex systems; hence physiologists are unlikely (unless they are working on essentially trivial problems) to find that molecular structures in isolation give more than partial insight into the problem under attack. ‘Explanations’ of physiological questions seem more likely to arise from combining such reductionist approaches with, on the one hand, thermodynamics and, on the other, control systems theory. Life depends on ‘non-equilibrium’ properties — i.e. on complex interactions that require the constant expenditure of energy to maintain them. And networks of information and control (the nervous system, hormones etc.) are central to the development, function, and probably the evolution of complex biological systems.

Seen in this way, the information encoded in the genes provides a very challenging experimental opportunity for physiologists. To have read the sequence of DNA is only a small step on the route to understanding how and to what extent our genes build and control our bodies, and cause disease. Genes do just one thing: they translate their information into proteins. To understand how the products of genes work individually and together to create the magnificent complexity of a whole organism is part of the exciting challenge that faces the revitalized science of physiology in the twenty-first century. Indeed, the prospects for physiology are wider still: it will ultimately need to link such understanding ‘upwards’ to such disciplines as experimental psychology, ecology and human biology.

Richard Boyd

Bibliography

Hodgkin, A. L. (1977). The pursuit of nature. Cambridge University Press, Cambridge.
Boyd, C. A. R. and and Noble, D. (1993). The logic of life: the challenge of integrative physiology. Oxford University Press, Oxford.

PHYSIOLOGY

PHYSIOLOGY can be traced back to Greek natural philosophy, yet in our age it has emerged as a sophisticated experimental science with numerous subspecialties. After distinction from its origins in the older discipline of anatomy, physiology encompassed study of physical and chemical functions in the tissues and organs of all living matter. Dynamic boundaries of the field are evident in that neuroscience, pharmacology, biophysics, endocrinology, and other scientific and medical specialties have roots in physiology. Given that plant physiology came to be defined as a specialization of botany, however, "physiology" today connotes the study of life-sustaining body functions and structures of animals, especially humans.

Development of Physiology in the United States

Scientific physiology in the United States developed slowly at first. Medical schools in the late eighteenth and early nineteenth centuries taught classes in physiology—then called the "institutes of medicine"—with no laboratory work being done. The earliest physiology professorship was founded in 1789 at the College of Philadelphia. Robley Dunglison, once a physician to Thomas Jefferson and one of a few full-time medical teachers at the time, wrote the subject's first comprehensive American textbook, Human Physiology,in 1832. William Beaumont (1785–1853) published a classic work on digestive function in 1833, given his opportunity to observe the subject in nineteen-year-old Alexis St. Martin, whose abdomen was blown open in a shotgun accident.

Prior to the Civil War (1861–1865), American physiologists were amateurs who tended to earn their livelihood through medical practice or teaching. Significant change in that state of affairs resulted from work by two pioneers of American physiology, John C. Dalton Jr. (1825–1889) and S. Weir Mitchell (1825–1914). As did many of their medical colleagues, Dalton and Mitchell traveled to Europe for postgraduate work, particularly in Paris, where they studied with physiologist Claude Bernard, famous for his carbohydrate metabolism research. Returning to the United States around 1851, Dalton eschewed a promising medical career, accepted a New York medical college professor's chair, and there became Amerrica's

first professional physiologist. Like his French mentor, Dalton was a strong proponent of experimental physiology and favored vivisection in his teaching, a practice that later placed him in controversy with early animal rights activists. Mitchell returned from Paris at the same time, settling in Philadelphia, where he failed in two significant efforts to secure a physiology professorship, due in part, as he saw it, to his expressed enthusiasm for the sort of experimental approach to the science he had learned in Europe. After serving as a surgeon in the Civil War, Mitchell's career turned toward excellent work in the study and treatment of neurological disorders, but he retained his devotion to physiology and eventually helped to found the science's first professional society.

Dalton and Mitchell's love for experimental physiology found fruition and institutional support in Henry P. Bowditch (1840–1911) and H. Newell Martin (1848–1896). Bowditch had studied in the prominent German school of physiology under Carl Ludwig, a master laboratory technician. As he returned to the United States in 1871, a reform movement in higher education fortunately called for more emphasis on experimentation, and Bowditch established America's first full-fledged physiology lab as a professor at the Harvard Medical School. Martin, a postgrad student in the prestigious British physiology school, was recruited by newly formed and well-endowed Johns Hopkins University, where he accepted a biology professorship and established a state-of-the-art physiology laboratory in 1876. In turn, Martin developed a mammalian heart preparation that led to important cardiac physiology discoveries. Fellowships allowed Martin to attract a bright cohort of students at Johns Hopkins, and, along with Bowditch and his students at Harvard, they founded physiology as an experimental research-based science in the United States.

Bowditch and Martin mentored a generation of physiologists who were eager, willing, and able to further the science, despite few gainful employment opportunities. They established new labs at the University of Michigan, Yale University, and Columbia University. Their professionalization of physiology coincided with medical education reforms calling for increased emphasis on experimental science and research. Thus the new physiology gained more than a foothold in medical schools; it became the preeminent discipline, leading to America's international prominence in biomedical science that has continued into the twenty-first century. In 1887, Bowditch and Martin heralded their scientific establishment to the world by founding the American Physiological Society (APS). Another original APS member, Johns Hopkins–educated William Howell, published his landmark American Textbook of Physiology in 1896. That was followed by initial circulation of the APS's prestigious American Journal of Physiology (AJP) in 1898.

Despite animal physiology's enhanced position, however, experimental biologists were not willing to concede the field. Replete with antagonism toward their counterparts in the 1880s, the biologists proposed a broader notion of physiology, combining the study of plants, zoology, microorganisms, and embryology toward a unified theory of life. These general physiologists, as they came to be known, found a leader in Charles Otis Whitman, who established a school for the broader science at the University of Chicago. The general physiology movement lost momentum around 1893, however, lacking broad institutional support and firm disciplinary structure. Although the Chicago school remained a haven for general physiologists, the medically oriented stream of animal physiology maintained power enough to define the term.

American Physiology in the Twentieth Century

Burgeoning into the twentieth century as well, American physiology achieved international ascendance during World War I (1914–1918). Progress in German and English labs was profoundly stifled by the war, while American physiologists continued their work in relative isolation. Even as new research continued, practical physiology was applied to submarine and aviation adaptation, troop nutrition, poison gas effects, munitions factory worker fatigue, wound shock, and other areas. Physiology continued to stimulate the medical field. Harvey W. Cushing, for example, a former student of Bowditch who also worked in the Johns Hopkins physiology lab, pioneered the practice of brain surgery. By all indications, including publications in the AJP and American research citations in international journals, American physiology was excellent.

Four physiologists stood out during the early to mid-twentieth century. Foremost among them was Walter B. Cannon (1871–1945), another former student of and eventual successor to Bowditch at Harvard. Among his achievements, Cannon used the new X-ray technology to advance understanding of digestive processes; he explained adrenal gland functions in response to emotional stress; and his classic work, The Wisdom of the Body, introduced a profound physiological principle, homeostasis. Not to forget the influence of his Textbook, William Howell (1860–1945) at Johns Hopkins did important heart research, described the pituitary gland, made momentous blood coagulation discoveries, and presided over the International Physiological Congress, which met in the United States in 1929. A. J. Carlson (1875–1956) at the University of Chicago was prolific in cardiac and gastric physiology research. Joseph Erlanger at Washington University in St. Louis, along with Herbert Gasser, won the 1944 Nobel Prize for research in nerve action, which incorporated valve amplification and introduced cathode ray tube technology, thus heralding the electronic age of physiological research.

A disciplinary orientation had developed in twentieth-century American physiology, emphasizing the study of intrinsic and extrinsic function, integration, and regulation of body systems over their structures. A talented

national field of scientists operating in well-funded programs thus undertook the study of metabolism, reproduction, muscular contractility, cardiopulmonary transport, regulation (for example, homeostasis), and how information is passed through the nervous system. This trend toward functional specialization, facilitated by advances in microscopy, imaging, and other technology, allowed physiological analysis to intensify from the level of entire bodies to specific organs, down to cells, and eventually to molecules. After many practical applications during World War II (1939–1945), American physiology expertise continued to gain during the Cold War, finding novel uses in the space program and especially in medical surgery. Latter twentieth century Americans enjoyed increased and enhanced life spans, if also rising health care costs. The heart and other vital organs, for example, could now be restored and even replaced; sexual function was demythologized; mental illness was treated with new drugs and lesser side effects; and nutritional information lowered cholesterol counts—all advances stemming from physiology research. Now given a vast array of subdisciplines, the specialization trend has separated the close association of physiology with medicine, although benefits to well-being are still claimed as justification for experimental research funding.

American physiology retains its world-class status achieved early in the twentieth century, evidenced by tens of Nobel Prizes in physiology and medicine awarded to U.S. citizens over the past thirty years. The work of Nobel winners Robert C. Gallo, Michael Bishop, and Harold E. Varmus, for example, led to the identification of retroviruses, which has proved invaluable in combating AIDS and even cancer. The simultaneous rise of sports and obesity in the United States has stimulated popular interest in exercise physiology. Aided by super computer technology and other American innovations, explosive recent discoveries in genetics, a field intimately related to physiology, promise monumental benefits, and moral controversies, to humankind. From its professional foundation in the latter nineteenth century to its status as a mature, expanding science in the new millennium, American study of animal body functions and structure (that is, physiology) promises further life-enhancing and perhaps even life-creating discoveries.

BIBLIOGRAPHY

The American Physiological Society. Home page at http://www.the-aps.org/.

Fye, Bruce W. The Development of American Physiology: Scientific Medicine in the Nineteenth Century. Baltimore: Johns Hopkins University Press, 1987.

Geison, Gerald L. Physiology in the American Context, 1850–1940. Baltimore: Williams and Wilkins, 1987.

Ronald S.Rasmus

See alsoLaboratories ; Medical Research ; Medicine and Surgery .

Physiology

Physiology is the study of how an organism and its body parts work or function normally. It is closely related to anatomy, which studies an organism's structure. There are different types of physiology, such as human physiology, plant physiology, and comparative physiology.

As a branch of biology that studies exactly how the different processes in living things work, physiology seeks to answer a more difficult question than its counterpart anatomy. Where anatomy wants to know how things are built, shaped, and how they fit together, physiology wants to know how something functions. For example, how does human lung tissue work? How can a seal survive underwater for ten minutes without taking a breath? How do camels survive so long without water? These and many other questions have been asked by people ever since they started to wonder about the natural world. In order to answer them, physiology must examine an organism's functions at several different structural levels.

At the simplest or chemical level, physiology studies atoms and molecules. The cellular level is next and focuses on cells, which are the smallest units of a living thing. In complex organisms like humans, groups of similar cells form tissues, resulting in the tissue level. An organ is composed of two or more tissue types that perform a certain function, and it is at the organ level that really complex functions take place. Organs that work together to accomplish a common purpose form an organ system. Together, all the organ systems make up the living body or the complete organism. This is the highest structural level, and each of the levels has its own physiology (functions). It is difficult if not impossible to study the body's functions without some knowledge of how it is built and organized (anatomy). Studying physiology without an understanding of anatomy would be like trying to understand how a car's engine works without having any idea what an engine looks like.

HISTORY OF PHYSIOLOGY

Physiology is thought to have first developed in the Greek Hippocratic school of medicine (before 350 b.c.). Around the same time, the Greek philosopher Aristotle (384–322 b.c.) stated that every part of the body is made for a purpose, and, therefore, that the function (physiology) of something can be figured out by learning its structure (anatomy). The publication that marks the beginning of modern physiology, On the Movement of the Heart and Blood in Animals, was published by the English physician, William Harvey (1578–1657), in 1628.

For nearly the next three centuries, physiology was closely associated with anatomy, and it was not until the nineteenth century that it became recognized as a separate discipline. By the middle of that century, discoveries suggesting the unity of all life (as well as the functions of all living things) led to the development of general physiology. This branch seeks to learn the physiological functions that are common to all living things. Comparative physiology is similar and tries to find the evolutionary connections between living things. One of the fundamental concepts of both is the notion of "homeostasis." This is the ability of an organism to function under very different conditions. Put another way, it is the ability of an organism to maintain an internal environment that compensates or corrects for changes that take place in its external environment. It is important to the survival of any organism that it be able to adapt quickly to its environment while at the same time keeping its internal functions and systems in a steady or balanced state. Control is another concept that is very important to physiologists. It is related to homeostasis and might be described as the way in which an organism's different systems communicate with and influence each other.

ARISTOTLE

Greek philosopher (a person who studies the source and nature of human knowledge) and naturalist Aristotle (384 b.c.–322 b.c.) is considered not only the greatest philosopher who ever lived but also the father of biology. His great interest in the natural world led him to closely observe living things and to classify them according to a system. He taught the world that true knowledge could be obtained by observation and experience.

Aristotle was born in Stagira, Macedonia, then a Greek colony north of Greece. His father was physician to the Macedonian king, Amyntas II. It is said that Aristotle lost both parents at an early age and was brought up by a family friend. At age seventeen, he traveled to Athens and joined Plato's Academy. Plato (c. 427 b.c.–c. 347 b.c.) was one of the greatest philosophers of all time, and Aristotle became his best pupil. When Plato died, Aristotle began a journey to various parts of the Greek world and was able to pursue his long-held interest in the natural world. The study of animals was his first love, and he began to systematically learn as much as could about them. However, in 342 b.c. he was called to Macedon by the new king, Philip II, the son of Amyntas II, to become tutor to his own young son named Alexander II (later called Alexander the Great). Aristotle schooled the young man for about six years until Alexander became king when Philip II was assassinated. When the new king began his own conquering campaigns, he no longer needed a tutor, and Aristotle returned to Athens. There he founded his own school he called the Lyceum, where he would do his research and give lectures. When Alexander II died in 323 b.c., however, Aristotle moved to his mother's hometown called Chalcis, where he died the next year.

Aristotle wrote on many subjects, from logic (the principles of reasoning) and ethics (the general nature of morality), to politics and biology. However, of all of his scientific writings, most consider his work in biology to be the most successful. To begin with, he was one of the first to look at animals in a scientific way. Always a careful observer, he eventually began to place all of the known animals in to some sort of order. This is called classification. After studying, observing, and even dissecting (cutting apart for anatomical study) them, Aristotle arranged more than 500 animals according to their physical similarities and tried to understand the relationships between them. Always an excellent observer, he noticed, for example, that dolphins give birth to live young, so he put them in with all of the land beasts (now known as mammals) despite the fact that they were considered fishes. He also dissected a great many animals and wrote about the complex stomach of cattle. His work on the developing embryo of the chick showed that this early phase of life was equally worthy of study. In his writings on biology, he first taught that the form of natural objects is determined by their purpose. This, he said, leads to the conclusion that the structures of organisms are determined by the functions they are supposed to serve. He also hinted at an idea of evolution (the process by which living things change over generations) because he arranged living things in a lower-to-higher order that suggested a sort of chain of progress.

While known today for his ethical and political writings, it was Aristotle who showed the earliest "natural philosophers," or scientists, that experience, observation, and experiment are necessary when one investigates the natural world. He regularly stressed the importance of theory being based on facts. For this and his regular observations, not to mention his love of the natural world, he is rightly called the father of biology.

HUMAN PHYSIOLOGY

Human physiology is the branch that studies how the human body and its parts work or function. Among the major functional systems studied are the integumentary system (the skin), the skeletal system (the framework), the muscular system (causing movement), the nervous system (control), the endocrine system (glandular control), the circulatory system (transport and delivery), the respiratory system (oxygen supply), the digestive system (breakdown and absorption of food), the urinary system (eliminating waste), and the reproductive system (to produce offspring). These highly organized and complex systems work together and contribute to what are called the necessary life functions. These are: movement (actively getting around), responsiveness (sensing and reacting to stimuli), digestion (breaking down food so it can be absorbed), metabolism (all the chemical reactions in cells), excretion (removing waste), reproduction (producing new life), and growth (increasing in size). Taken together, these are the internal processes and functions that maintain life, the study of which is physiology.

While human physiology is of great value to medicine, plant physiology is most useful to agriculture and forestry. However, whether the type of physiology studied is that of plants or animals, it is important to know how a living organism works normally or is supposed to function, since only then can one determine if something is wrong and what might be done to correct the problem. Without the knowledge of anatomy, physiology would not be as useful as it now.

[See alsoBrain; Circulatory System; Digestive System; Endocrine System; Excretory System; Heart; Integumentary System; Muscular System; Nervous System; Reproductive System; Respiratory System; Skeletal System ]