The Life Sciences Recent Progress and Application to Human Affairs The World of Biological Research Requirements for the Future (1970) / Chapter Skim
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Chapter 2: Biology in the Service of Man- Biological Research and Medical Practice
Chapter 2: Biology in the Service of Man- Biological Research and Medical Practice
Pages 142-176
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From page 142... ...
Only a small sampling can be offered here, but it should become evident that the life sciences have dramatically altered our life style, contributing to our security, our health, our comfort, and our enjoyment. BIOLOGICAL RESEARCH AND MEDICAL PRACTICE The impressive and rapidly growing, though fragmentary?
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From page 143... ...
Thus, vitamin-deficiency diseases e.g., pellagra, beriberi, sprue, and scurvy were the clues to the very existence of vitamins and, hence, to the coenzymes of metabolism; investigations of diabetes and glycogen-storage diseases revealed the hormonal control of carbohydrate metabolism and, indeed, the pathways of that metabolism; the prevalence of pernicious anemia revealed the existence of vitamin Be., and of the unique biochemical reactions it makes possible; the requirement for agents to manage infectious diseases stimulated the discovery of antibiotics, and these, in turn, proved to be powerful tools in the elucidation of the mechanism of operation of the genetic apparatus and the synthesis of bacterial cell walls; the dramatic changes in the volume, pH, and salt concentrations of blood plasma in such disorders as infantile diarrhea, pernicious vomiting, diabetic coma, and Addison's disease have been both the primary stimuli and the major "experiments" in revealing the complex homeostatic mechanisms that control the volume, acidity, and electrolyte composition of the body fluids of both the intracellular and extracellular compartments; the variety of cardiac disorders has revealed the fine mechanisms and neural control of the cardiovascular system; and the existence of sickle cell anemia and other instances of altered hemoglobin structure were the first demonstration that a "point" mutation results in a specific amino acid replacement in a protein, as well as the demonstration that the genetic code in man must be identical with that in the bacterial species in which it was first determined. In each instance, the knowledge so gained, abetted by insights from other areas of biology, has resulted in expansion and improvement of the therapeutic armamentarium to the great benefit of those afflicted with the very disorders that served as clues.
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From page 144... ...
The combined death rate (deaths per 100,000 of population) from these diseases was greater than that from heart disease today, a malady that killed more than 712~000 persons in 1965, when cancer took the lives of an additional 300,000 individuals.
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From page 145... ...
The discovery of specific bacterial inhibition has a long history. In 1904, Paul Ehrlich, a German scientist, postulated that infectious diseases could be treated if chemicals could be found with a greater affinity and toxicity for parasite organisms than for host cells.
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From page 146... ...
After elucidation of the chemical structure of penicillin, in due course natural penicillin was replaced by semisynthetic penicillins, which are comparatively simple to manufacture and which retain the essential molecular configuration of the parent molecule, which is so eRective against Gram .
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From page 147... ...
Prior to 1940, thousands of hospital beds were occupied by patients with infectious diseases. Today, in the main, these patients receive a prescription for antibiotics and return home.
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From page 148... ...
is subject to allosteric feedback inhibition by the final product, which bears little resemblance to the sub strate of the enzyme responsible for the committed step. It is clear that ingestion of cholesterol drastically inhibits its own biosynthesis.
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From page 149... ...
A generation will be required to establish whether the dosage schedules suggested by the new mathematical model, which, far more than in the past, mimics the release of pancreatic insulin by normal individuals, will also prevent the physical deterioration that is characteristic of diabetics treated with insulin for the last half century. As understanding of disease has dramatically increased, so have demands for better comprehension of what disease is on the molecular level.
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From page 150... ...
This coat is shed as the nucleic acid enters the cell, where it usurps the normal genetic apparatus, shutting off normal production of cellular RNA and proteins so as to turn out many copies of the virus itself. Patently, any drug or procedure calculated to interfere with this process must also similarly interfere with normal operation of the genetic apparatus.
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From page 151... ...
This may yet prove to be the basis of a truly useful clinical approach to viral infection with the happy property of being generally useful without regard to the specific virus in question in any riven patient. CANCER THERAPY Insights into the nature of DNA, its biosynthetic processes, and its role in cell growth and development have had wide application in recent cancer research.
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From page 152... ...
The turnover of normal cells, however, is distinctly less than that of rapidly dividing cancer cells; in weighing risk versus benefit, it was concluded that the toxic effects of methotrexate are less than its benefits, particularly in the treatment of leukemia. Another agent in the arsenal of anticancer agents is actinomycin, originally found as an antibiotic, which checks cell growth by limiting RNA synthesis on DNA.
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From page 153... ...
The other 10 can be synthesized by most human cells, but some cells rely on receipt of such amino acids in the blood after they have been synthesized by the liver. Asparagine is one such amino acid.
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From page 154... ...
The major question before all those concerned with cancer therapy is the underlying nature of the neoplastic transformation of previously normal cells. It has long been known that many physical agents-e.g.
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From page 155... ...
In the course of essentially negative experimental trials with allopurinol in cancer victims, it was observed that, during treatment with this drug, patients excreted unusually small amounts of uric acid. That the measurement was made at all derived from the fact that allopurinol was synthesized as an antimetabolite of the purines required for synthesis of RNA and DNA;
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From page 156... ...
Because of this structural similarity to hypoxanthine, allopurinol can attach to xanthine oxidase, the enzyme that catalyzes formation of uric acid and can inhibit its normal activity. In consequence, daily formation of uric acid is much reduced, while the hypoxanthine is disposed of by an alternative process, viz., reutilization for nucleic acid synthesis.
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From page 157... ...
is the only specific biological alteration one can temporally associate with the evolutionary appearance of the primates, and one cannot help but wonder whether the presence of uric acid in the blood is in some manner related to the subsequent rapid evolutionary development of the brain. GENETIC DISEASES The first scientist to document the fact that some diseases tend to run in families was A
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From page 158... ...
Catalase Fibrinogen y-Globulin Tyrosinase Homogentisic Acid Oxidase Serum Albumin Argininosucc~nase Uridine Diphosphate Glucuronate Transferase Glucose-6-Phosphate Dehydrogenase Fructose-1-Phosphate Aldolase Fructokinase Galactose-1-Phosphate Uridyl Transferase Iodotyrosine Dehalogenase Hypoxanthine Guanine Phosphoribosyl Transferase Tryptophan Pyrrolase Hemoglobins Pyruvate Kinase Antihemophilic Factor A Antihemophilic Factor B Histidase Cystathionine Synthetase Alkaline Phosphatase Isovaleryl CoA Dehydrogenase Amino Acid Decarboxylase Methemoglobin Reductase Orotidine 5'-Phosphate Pyrophosphorylase Accelerator Globulin ~-Xylulose Dehydrogenase Phenylalanine Hydroxylase Sulfite Oxidase Ceruloplasmin Xanthine Oxidase doubtedly genetic alteration of vital processes exists, but is expressed not as defined disease but as complete lethality with failure of the fertilized egg to develop. With few exceptions, all these diseases reflect the presence of the mutant gene in the chromosomes of both parents; hence there is the great potential of genetic counseling in the future to limit such diseases.
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From page 159... ...
Gaucher's Disease Niemann-Pick Disease Porphyria Tangier Disease Tay-Sachs Disease Failure to digest and/or absorb lipid Thick viscous mucous secretion, high sodium content of all secretions Excretion of cystine, lysine, arginine, and ornithine Inability to utilize amino acids, notably cystine; aberration of amino acid transport into cells Increased excretion of amino acids Excessive excretion of chondroitin sulfate B Accumulation of cerebrosides in tissues Accumulation of sphingomyelin in tissues Increased excretion of uroporphyrins Lack of plasma high-density lipoproteins Accumulation of gangliosides in tissues understanding in the last few decades, it would have been impossible to detect and define this list of defects in man's own essential biology or to arm genetic counselors in the future. Examination of individuals with inborn errors has contributed significantly to understanding of normal metabolism.
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From page 160... ...
Immunity is a highly specific condition in which, having produced antibodies to the toxins produced by bacteria or to the exterior of bacteria and viruses animals are not adversely affected by their invasion. The system responsible for antibody formation occupies the current scientific limelight because, if it could be understood and controlled, the possibility of victory over cancer and infectious diseases would be markedly enhanced while one of the major stumbling blocks to organ transplantation would be overcome, and because, intrinsically, it is a fascinating process.
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From page 161... ...
Particularly intriguing is the mechanism whereby the antigen, or a derivative generated in a macrophage, causes the formation of the highly specific antibody. Antibodies are large protein molecules constructed, as usual, of amino acids, according to the plan shown in Figure 31.
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From page 162... ...
L = light chains; H = heavy chains; CHO = carbohydrate unit. The variable and constant portions of the chains, with respect to amino acid sequences, are indicated by the labels V and C, respectively.
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From page 163... ...
Acute and chronic kidney disease develops in persons who make antibodies against their own kidneys. Rheumatic fever and damaged heart valves appear in patients whose antibodies fight their own myocardial muscle fibers.
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From page 164... ...
First came procedures whereby, from the behavior of an injected pulse of an indicator dye, one could calculate blood Dow. Twenty years later, it was shown that thin, radiopaque catheters could be introduced into the heart chambers via peripheral blood vessels and carefully positioned visually by huoroscopy, permitting direct sampling of blood in the cardiac chambers.
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From page 165... ...
With them the physician can make a highly precise diagnosis, establish the quantitative as well as the qualitative nature of the problem, and rationally decide upon a therapeutic or surgical course. One of the more remarkable aspects of the surgical technique is the recent capability to literally patch major blood vessels and cardiac valves, thanks to the availability of suitable, nonreactive plastics from the chemical industry.
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From page 166... ...
By means of this technique and associated studies, it became possible to characterize the ionic basis of cardiac electrical activity, to identify the unique properties of certain specialized cells, and to observe the influence of, for example, quinidine and digitalis on these parameters. Now, from studies of the electricity of the heart and of the ionic processes associated with it, highly detailed, though not yet complete, pictures have been drawn of each of the major clinical types of arrhythmia, a new beginning is under way, and suitable test systems are available for the search for specific antiarrhythmic drugs.
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From page 167... ...
Artificial heart valves and plastic blood vessels, developed in collaboration with engineers, are available to surgeons. Even totally implantable artificial hearts have been tried in man.
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From page 168... ...
When carbonic anhydrase was then found to be present in quantity in the kidney, it became apparent that this enzyme plays a role in kidney mechanisms for excretion of acid and that sulfanilamide's inhibitory effect on the kidney enzyme accounted for its effect on urinary secretion, with consequent acidosis. Accumulation of acid is the consequence of excretion of sodium ions.
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From page 169... ...
, which, in 1950, became the first useful oral diuretic. Incidentally, it also became a remarkably successful agent for treatment of glaucoma, excessive secretion of fluid into the anterior chamber of the eye, by interfering with the carbonic anhydrase of the overactive secretory cells.
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From page 170... ...
The component of medical practice that makes the greatest demands on our resources measured in the time of physicians, nurses, paramedical personnel, hospital beds, and the ever more complex technology of intensive medical care is the management of those disorders for which research has, to date, made possible only palliative or physiologically corrective measures, termed by some "half-way medical technologies." When research has provided a definitive therapeutic or preventive regimen, it is invariably cheaper and simpler than the palliative treatment previously available for the same disease. This is surely true for a wide range of infectious diseases such as lobar pneumonia, poliomyelitis, tuberculosis, bacterial endocarditis, typhus, typhoid fever, and diphtheria, to name but a few.
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From page 171... ...
Grim prospect indeed! Population Control While biomedical scientists pursue greater sophistication in the understanding and treatment of disease, this attempt must be matched by a concerted effort to solve the crisis being brought on by the continuing increase in human population.
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From page 172... ...
This is available in urine, and a modest supply now permits pregnancy for many childless wives. But the supply is limited and one must await precise establishment of the amino acid sequence of this hormone, followed by synthesis using the recently developed methods for polypeptide synthesis, to overcome this shortage.
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From page 173... ...
The great expense of the necessary prolonged procedures is a serious deterrent to the undertaking of such activity by the drug manufacturers, who must somehow be assured that they will at least recover their investment. Meanwhile, the needs of humanity are so great that we suggest
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From page 174... ...
Whereas a significant fraction of infant mortality may be eliminated by applying available understanding, further progress will be entirely dependent on improved knowledge of the entire process from conception to the early years of life. No problem appears more urgent than definitive establishment of the consequences in later life of early nutrition.
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From page 175... ...
Can this clockwork be reset? One prominent theory of aging holds that it reflects a developed instability of the genetic apparatus of individual cells, i.e., that aging occurs
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From page 176... ...
Current efforts utilize mammalian cells in tissue culture and such organisms as the thousand-celled rotifer. A suitable test model should have a short life-span and well-established standardized nutritional requirements, should be maintained in freedom from infections and other external insults, and must possess genetic uniformity.
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