Table of Contents
Biochemistry and medicine enjoy a mutually cooperative relationship. Biochemical studies have illuminated many aspects of health and disease, and the study of various aspects of health and disease has opened up new areas of biochemistry. The medical relevance of biochemistry both in normal and abnormal situations is emphasized throughout this book. Biochemistry makes significant contributions to the fields of cell biology, physiology, immunology, microbiology, pharmacology, and toxicology, as well as the fields of inflammation, cell injury, and cancer. These close relationships emphasize that life, as we know it, depends on biochemical reactions and processes.
Biochemistry began with the discovery that a cell-free extract of yeast can ferment sugar
The knowledge that yeast can convert the sugars to ethyl alcohol predates recorded history. It was not, however, until the earliest years of the 20th century that this process led directly to the science of biochemistry. Despite his insightful investigations of brewing and wine making, the great French microbiologist Louis Pasteur maintained that the process of fermentation could only occur in intact cells. His error was shown in 1899 by the brothers Buchner, who discovered that fermentation can indeed occur in cell-free extracts. This revelation resulted from the storage of a yeast extract in a crock of concentrated sugar solution added as a preservative. Overnight, the contents of the crock fermented, spilled over the laboratory bench and floor, and dramatically demonstrated that fermentation can proceed in the absence of an intact cell.This discovery made possible a rapid and highly productiveseries of investigations in the early years of the 20th centurythat initiated the science of biochemistry. These investigations revealed the vital role of inorganic phosphate, ADP, ATP, and NADP(H), and ultimately identified the phosphorylated sugar and the chemical reactions and enzymes (Gk “in yeast”) that convert glucose to pyruvate (glycolysis) or to ethanol and CO2(fermentation). Subsequent research in the 1930s and 1940sidentified the intermediates of the citric acid cycle and of urea biosynthesis, and provided insight into the essential roles of certain vitamin-derived cofactors or “coenzymes” such as thiamin pyrophosphate, riboflavin, and ultimately coenzyme A, coenzyme Q, and carbamide coenzymes. The 1950s revealed how complex carbohydrates are synthesized from, and broken attention to the molecular mechanisms involved in the control of normal cell growth. These examples illustrate how the study of disease can open up areas of basic biochemical research. Science provides physicians and other workers in health care and biology with a foundation that impacts practice, stimulates curiosity, and promotes the adoption of a scientific approach to continued learning. So long as medical treatment is firmly grounded in the knowledge of biochemistry and other basic sciences, the practice of medicine will have a rational basis capable of accommodating and adapting to new knowledge. down to simple sugars, and delineated the pathways for biosynthesis of pentoses and the breakdown of amino acids and lipids. Animal models, perfused intact organs, tissue slices, cellhomogenates, and their subfractions, and purified enzymesall were used to isolate and identify metabolites and enzymes. advances were made possible by the development in the late 1930s and early 1940s of techniques such as analytical ultracentrifugation, paper, and other forms of chromatography, and the post-World War II availability of radioisotopes, principally 14C, 3H, and 32P, as “tracers” to identify the intermediates in complex pathways such as that leading to the biosynthesis of cholesterol and other isoprenoids and the pathways of amino acid biosynthesis and catabolism. X-ray crystallography was then used to solve the three-dimensional structure, first of myoglobin, and subsequently of numerous proteins, polynucleotides, enzymes, and viruses including that of the common cold. Genetic advances that followed the realization that DNA was a double helix include the polymerase chain reaction, and transgenic animals or those with gene knockouts. The methods used to prepare, analyze, purify, and identify metabolites and the activities of natural and recombinant enzymes and their three-dimensional structures are discussed in the following chapters.
Biochemistry and medicine have stimulated mutual advances
The two major concerns for workers in the health sciences—and particularly physicians—are the understanding and maintenance of health and the understanding and effective treatment of disease. Biochemistry impacts both of these fundamental concerns, and the interrelationship of biochemistry and medicine is a wide, two-way street. Biochemical studies have illuminated many aspects of health and disease, and conversely, the study of various aspects of health and disease has opened up new areas of biochemistry (Figure 1–1). Knowledge of protein structure and function was necessary to identify and understand the single difference in amino acid sequence between normal hemoglobin and sickle cell hemoglobin, and analysis of numerous variant sickle cell and other hemoglobins has contributed significantly to our understanding of the structure and function both of normal hemoglobin and of other proteins. During the early 1900s, the English physician Archibald Garrod studied patients with the relatively rare disorders of alkaptonuria, albinism, cystinuria, and pentosuria and established that these conditions were genetically determined. Garrod designated these conditions as inborn errors of metabolism.
His insights provided a foundation for the development of the field of human biochemical genetics. A more recent example was the investigation of the genetic and molecular basis of familial hypercholesterolemia, a disease that results in early-onset atherosclerosis. In addition to clarifying different genetic mutations responsible for this disease,this provided a deeper understanding of cell receptors and mechanisms of uptake, not only of cholesterol, but of how other molecules cross cell membranes. Studies of oncogenes and tumor suppressor genes in cancer cells have directed attention to the molecular mechanisms involved in the control of normal cell growth. These examples illustrate how the study of disease can open up areas of basic biochemical research.Science provides physicians and other workers in health care and biology with a foundation that impacts practice, stimulates curiosity, and promotes the adoption of scientific approaches for continued learning. So long as medical treatment is firmly grounded in the knowledge of biochemistry and other basic sciences, the practice of medicine will have a rational basis capable of accommodating and adapting to new knowledge.
Normal biochemical processes are the basis of health
Biochemical Research Impacts Nutrition and Preventive Medicine
The World Health Organization (WHO) defines health as a state of “complete physical, mental, and social well-being and not merely the absence of disease and infirmity.” From a biochemical viewpoint, health may be considered a situation in which all of the many thousands of intra- and extracellular reactions that occur in the body are proceeding at rates commensurate with the organism’s survival under pressure from both internal and external challenges. The maintenance of health requires an optimal dietary intake of a number of chemicals, chief among which are vitamins, certain amino acids, and fatty acids, various minerals, and water. Understanding
nutrition depends to a great extent on the knowledge of biochemistry, and the sciences of biochemistry and nutrition share a focus on these chemicals. Recent increasing emphasis on systematic attempts to maintain health and forestall disease, preventive medicine includes nutritional approaches to the prevention of diseases such as atherosclerosis and cancer.
Most Diseases Have a Biochemical Basis
Apart from infectious organisms and environmental pollutants, many diseases are manifestations of abnormalities in genes, proteins, chemical reactions, or biochemical processes, each of which can adversely affect one or more critical biochemical functions. Examples of disturbances in human biochemistry responsible for diseases or other debilitating conditions include electrolyte imbalance, defective nutrient ingestion or absorption, hormonal imbalances, toxic chemicals or biologic agents, and DNA-based genetic disorders. To address these challenges, biochemical research continues to be interwoven with studies in disciplines such as genetics, cell biology, immunology, nutrition, pathology, and pharmacology. In addition, many biochemists are vitally interested in contributing to solutions to key issues such as the ultimate survival of mankind and educating the public to support the use of the scientific method in solving environmental and other major problems that confront us.
Impact of the Human Genome Project on Biochemistry, Biology, & Medicine
Initially, unanticipated rapid progress in the late 1990s in sequencing the human genome led in mid-2000 to the announcement that over 90% of the genome had been sequenced. This effort was headed by the International HumanGenome Sequencing Consortium and by Celera Genomics, a private company. Except for a few gaps, the sequence of the entire human genome was completed in 2003, just 50 years after the description of the double-helical nature of DNA by Watson and Crick. The implications for biochemistry, medicine, and indeed for all of biology, are virtually unlimited. For example, the ability to isolate and sequence a gene and to investigate its structure and function by sequencing and “gene-knockout” experiments have revealed previously unknown genes and their products, and new insights have been gained concerning human evolution and procedures for identifying disease-related genes. Major advances in biochemistry and understanding human health and disease continue to be made by mutation of the genomes of model organisms such as yeast and eukaryotes such as the fruit fly Drosophila melanogaster and the roundworm Caenorhabditis elegans. Each organism has a short generation time and can be genetically manipulated to provide insight into the functions of individual genes. These advances can potentially be translated into approaches that help humans by providing clues to curing human diseases such as cancer and Alzheimer’s disease. Figure 1–2 highlights areas that have developed or accelerated as a direct result of progress made in the Human Genome Project (HGP). New “-omics” fields have blossomed, each of which focuses on comprehensive study of the structures and functions of the molecules with which each is concerned. Definitions of these -omics fields mentioned below appear in the Glossary of this chapter. The products of genes (RNA molecules and proteins) are being studied using the techniques of transcriptomics and proteomics. A spectacularexample of the speed of progress in transcriptomicsis the explosion of knowledge about small RNA molecules asregulators of gene activity. Other -omics fields include glycomics,lipidomics, metabolomics, nutrigenomics, and pharmacogenomics.
keep pace with the information generated, has received much attention. Other related fields to which the impetus from the HGP has carried over are biotechnology, bioengineering, biophysics, and bioethics.Nanotechnology is an active area, which, for example, may provide novel methods of diagnosis and treatment for cancer and other disorders. Stem cell biology is at the center of much current research. Gene therapy has yet to deliver the promise that it appears to offer, but it seems probable that ultimately will occur. Many new molecular diagnostic tests have developed in areas such as genetic, microbiologic, and immunologic testing and diagnosis. Systems biology is also burgeoning. The outcomes of research in the various areas mentioned above will impact tremendously the future of biology, medicine, and the health sciences. Synthetic biology offers the potential for creating living organisms, initially small bacteria, from genetic material in vitro that might carry out specific tasks such as cleansing petroleum spills. All of the above make the 21st century an exhilarating time to be directly involved in biology and medicine.