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Genetic and Molecular Basis of Human Hereditary Diseases J. Edwin See gmiller A fresh view of some old and new diseases recognized by means of modern genetics and biochemistry. A. N AREA of significant medical progress over the past decade has been the recognition and the biochemical characterization of an ever-increasing number of human hereditary diseases (1). Some of the practical consequences have been the development biochemical methods for more these diseases (many of them new approaches for treatment types of mental hopeless medical retardation curiosities. clinical laboratories terminations gives of genetically of that The have, in time past, prospect of more of automated analytic promise of the detection determined objective chemical and precise diagnoses of a large number of newly recognized) and the opening of of clinical disorders including some abnormalities been regarded widespread use as in systems for chemical deof aim even larger number of body chenmistry in the years ahead. Although many of these inherited diseases are relatively rare disorders, there are considerations that cause these disorders to assume a far greater importance to the medical and scientific community than is revealed by their statistical incidence. Basic Concepts Gene-Enzyme Relationship These portunities disorders are experiments of nature that for expanding our knowledge of many present basic unique biologic opproc- esses. Some of our fundamental concepts of the mechanism of gene action can be traced to basic studies of human hereditary diseases. From his studies of the rare human metabolic disease aleaptonuria, the BritProm Metabolic the Section on Human Biochemical Genetics, National Institute of Arthritis Diseases, National Institutes of Health, U. S. Public Health Service, Bethesda, and Md. 20014. Presented as part AAAS, Washington, of the symposium P. 0., Dec. 26-30, “Inborn 1966. Errors 554 of Metabolism,” 133rd Annual Meeting, - Vol. 14. No. 7, 1967 ish physician HUMAN Archibald HEREDITARY Garrod proposed enzyme relationship in 1908 (2), over ment by microbiologists (3, 4). With largely by microbial genetics, this mechanisms gene amino or cistron controls the chain (5, 6). Another inherited human acid the basic concept before its 30 years further concept for one of the fundamental 555 DISEASES has of the genefull develop- refinements become contributed time basic premise of gehle action ill which a single sequence of a single polypeptide disease, sickle cell anemia, has provided an even more basic example of the more detailed mechanism by which gene action can produce a disease. Substitution of a single anliflo acidvaline for glutamic acid-in the 6 position of time beta chain of the hemoglobin molecule gives rise to sickle cell hemoglobin which has different physical properties from normal hemoglobin (7, 8). The tendency of the sickle cell hemoglobin to form aggregates when deprived of oxygen is the primary cause of the red blood cell destruction and occlusion of the small blood vessels that characterize this disease to the clinician. Among the possible genetic codes for valine and glutamic acid (9), codes can be found that differ by only one base, suggesting the possibility that the mutation responsible for hemoglobin may have been a single substitution molecule directing synthesis of the beta chain ing to the sixth amino acid. the appearance of this of one base in the DNA at a position correspond- Mutations The above example provides a model for our thinking of one of the mechanisms by which genetic differences are expressed. In time simplest type of structural gene mutation, a relatively minor alteration in the base sequence of one small portion of the DNA molecule directing the assembly of a polypeptide chain could thereby be expected to produce an altered protein. If the protein product of time gene action happens to be an enzyme, and time substitution occurs at or near the active binding site for time substrate, the resulting protein may he expected to have a diminished or absent enzyme activity. A defect in a regulator gene that controls the activity of a structural gene can produce a similar deletion of an enzyme in bacterial systems (in). Comparable regulator genes in mammalian cells have been postulated hut are yet to be demonstrated conclusively-. The enzyme deletion, in turn, introduces a chemical aberration in cellular metabolism which may be reflected in bacterial mutants by alterations in growth or in nutritional requirements. In the human species, such biochemical mutations can produce a metabolic disease (1). Genetic mutations produced in microorganisms at will have provided 556 EEGMILLE Clinical Ckemstry powerful tools for increasing our knowledge of the operational details of basic genetic and biochemical processes in these organisms (ii, 1.2). Only in the human species do we find any significant imumber of wellcharacterized genetic biochemical deletions in higher life forms that might serve comparable roles in aiding the study of these basic genetic processes in mammaliaim cells. It seems ulilikely that this reflects a higher incidence of genetic mutation in maii, but rather, more intensive study of our own species and, in particular, the interest of physicians in the diseases that have resulted from some of these processes. Diagnostic Procedures Past As might be expected, the classic metabolic diseases, the so-called “inborn errors of metabolism” that were first. recognized were brought to the attention of the physician by reason of the accumulation of abnormal chemical substances which the physician could detect with his five senses. One can feel and see time (leposits of crystals of sodium urate that constitute the tophi located in and about time joints in patients with gouty arthritis, the clinical features of which were first described by Hippocrates around the 4th century, B.C.; and, of course, the sweet taste of glucose has provided an unaesthetic but, nevertheless, useful test of the urine for diabetes since the 17th century-long before chemical tests were available to the physician. In alcaptoimuria, a rare disorder first definitely described a century ago, one can see the blackening of the infant’s urine on the diapers caused by the oxidation by air of homogentisic acid, a chemical relative of photographic developer, which is excreted in large quantities throughout the life of the individual. It was only 30 years ago that the unusual odor of the urine of a mentally deficient child led the Swedish chemist Foiling to isolate phenylpyruvic and phenylaeetic acid from the urine, thereby permitting the chemical detection of the disease we now know as phenyiketonuria (‘i). A by-product of the increasing use of chemical tests of biologic fluids to aid in the diagnosis of disease has been the detection of chemical abnormalities in a continually increasing number of clinical disorders and even in individuals without clinical symptoms. Many of these disorders have been detected because of the lack of specificity of many of the chemical tests in routine use. An ironic result of the “progress” in substitution of more specific tests is the inability to detect many of these cbemieal abnormalities, As an example, homogentisic acid gives a V01. 14, o. 7, 1967 HUMAN HEREDITARY 557 DISEASES strong reducing action with the alkaline copper solutions that have been in use in the past for detecting sugar in urine. In fact, some alcaptonuric patients have been treated with insulin for diabetes on the basis of this test. This erroneous diagnosis would have been avoided if the clinical chemist performing the test had been observant and had noted that the fluid overlying the red copper oxide was black instead of blue or green. With the use of more specific methods for the routine detection of glucose in urine, the ability to detect alcaptonuria has been lost and patients with this disorder have gone undetected by this specific chemical test. Present and Future There is good reason to expect that genetically determined differences in body chemistry will be detected at an increasing rate during the years immediately ahead of us. This should come about through the routine determination of an increasing number of chemical components of body fluids in a progressively larger portion of the patient population as an objective aid to the clinician in his detection of disease. Such widespread use of chemical determinations is being made possible by the use in clinical laboratories of automated analytic equipment for chemical determinations. Once an abnormal substance is noted, its identification then permits intensive studies of not only the basic enzyme defect giving rise to this substance but also the way by which the chemical aberration produces the clinical manifestations of the metabolic disease. At the present time there is no way of effecting a true cure of these diseases by correcting the defect in the gene. Nevertheless, these findings have provided new understanding of the disease process and given new hope for successful treatment of a remarkable array of diseases that have, until recently, been completely untreatable. Basic Metabolic Defects A detailed catalog of the phenomenonally metabolic defects that have been characterized among hereditary diseases is not possible ever, a few examples of these diseases, the biochemical defect gives rise to the disease that leads to the successful treatment of an diseases will be discussed. The proteins formed by time cell serve one large imumber of basic during the past decade in this presentation. Howgeneral ways by which the process, and the rationale increasing number of these of two grleral functions- 558 SEEGMILLER Clinical Chemstry either as units of structure or as units of biochemical function, mostly in time form of enzymes which catalyze specific chemical reactions. These reactions are performed in a detailed sequence within the cell, somewhat allalogous to a factory production line. The failure of an enzyme in the metabolic sequence to perform its function results iii the accumulation of the unreacted metabolite. It cannot proceed along that particular production line for further processing. The interruption of some of the metabolic pathways results in a situation that is incompatible with life, and it is thought that this situation may account for some of the spontaneous abortions or deaths in the first few weeks or months of life, lithe interruption of metabolism is not a complete disaster to life, it can result in a wide variety of clinical expressions ranging from simple failure of a child to thrive, to production of disease late iii adult life. In still other conditions, such as pentosuria, the defect seems to have no detectable deleterious effect whatever, and is called a disease only by courtesy. Ochronotic Arthritis and Alcaptonuria In some diseases, the pathologic effects result from time conmpound that accumulates. Two types of arthritis can he explained by this mechanism. The classic metabolic disease alcaptollliria already mentioned produces no discernible ill effects for the first 30 years or so of a patient’s life. For many years it was regarded as a medical curiosity. It was in 1904 that Sir William Osler at Johns Hopkins Hospital made the first clinical association of this medical curiosity with a puzzling type of artlmritis. Timis disorder ochronotic arthritis begins jim adult life and usually involves the spine and other major joints; postmortem examination reveals the deposition of a black pigment in and about the bones and cartilage. Undoubtedly, our ability to make time association of the artimritis with the abnormal metaholite was greatly facilitated l)y the tendency of homogentisic acid to form pigmented products that can be readily seen. It is conceivable that other types of hereditary arthritis could arise from metabolites with equally deleterious effects on joint cartilage which do not announce their presence by pigment formation and so, remain unrecognized. We have already mentioned Archibald Garrod’s studies of this disease in wimich he formulated the first rational hypothesis to account for what he named ‘‘ml)orn errors of metabohisni’’ (2). ITe proposed that homogentisic acid accumulates in these patients because they lack an enzyme that normally degrades it. It was not until 1958 that there was Vol. 14, No. 7, 1967 an o)portui1ity to lest required surgery for tioii, a sinai! piece of sequence of enzymes tioii and time disposal gentisic acid oxidase enzymes that degrade patient HUMAN HEREDITARY 559 DISEASES G arrod ‘s hypothesis. A 1)atiClit wilhi a leal)toituria uncontrollable gastroilitestillal l)leedillg. At ol)efllhis liver was removed for l)iocllemlcal studies. The that are normally responsible for both time formaof imomogentisic acid were studied (14). Honmowas the only enzynie absent from the series of tyrosiime, providing concrete evidence in this of time correctness of (Jarrod’s hypothesis. Phenylketonuria and Tyrosinemia Other absence results defects in this metabolic sequence are now knowii. Tinis, the of time enzyme for formation of tyrosilie from pimenylalanine iii the metabolic disorder )lmeny1ketonuria, with its accom- mental deficiency (1). Another disorder, tyrosillemia, has recently been characterize(l as a defect in the enzyme p-hydroxyphenylpyruvic acid oxidase respolmsible for tile formation of homogentisic acid (is). The clinical manifestations of timis (hisol’der are entirely different from the other two and consist of renal tubular dysfunction and a severe cirrhosis of time liver, leading to early death in many l)atie1ts unless special treatment is instituted (16, 17). I)allyiIlg Gout Ammother enzyme deletion, which is presunied to have occurred Ill a remote ancestor of both mait aimd the higher apes, has left time whole human species heir to the gout. 1mmall other mammals, the enzyme uncase is present and degrades uric acid to its nmueim more soluble end product, ahlantoimi, for excretion. In addition, the human kidney excretes uric acid inefficiently. As a result, time mean colicentration of mirate in human serum is quite iear time tlmeoretical liniit of solul)ihity of urate (18). A portion of the hyperuriceniic iil(livi(luals (leposit time sparingly soluble urate crystals in and about time joints which can give rise to erosion of joints and episodes of iimflammatory reaction clmaracteristics of the acute attack of gouty arthritis (19). Glycogen Storage Disease Disease produce disease. in the human can also result from a needed product, as is the situation Here, there is absence of time liver failure in Type of the enzyme to I glycogeim storage enzyme glucose-6-phospha- tase, which is responsible for the production of most of the blood sugar from glycogen (20). As a result, jimchildhood these patients have severe episodes of hypoglycemia, producing weakness fainting, and severe 560 SEEGMILLER Clinical Chemistry episodes of ketosis. If they do live to adult life, a surprising number have been found to develop gouty arthritis (21). The precise mechanism by which this defect in carbohydrate metabolism causes hyperuricemia and gout is another example of insights derived by studying these disorders. These patients have a lacticacidemia and ketonemiaboth of which can cause a renal retention of uric acid. In addition, they have an excessive purine biosynthesis (22). A biochemical link between carbohydrate metabolism and punimme metabolism can be made in the formation of 5-phosphoribosyl-1-pyrophosphate (PRPP), which is one of the two reactants of time first enzymatic reaction uniquely committed to purine synthesis: Phosphoribosylpyrophosphate + glutamine - phosphoribosylamine This reactioim is rate-linmiting in the control of purine but aim increased quaimtity of PRPP in cells of patients glycogen storage disease has not yet been demonstrated. Nutritional + pyrophosphate biosynthesis, with Type I Diseases A similar type of eimzyme deletion can also be used to explain some of the imutnitional diseases. Both the human and time guinea pig lack the enzyme which, iii all other mammals, catalyzes the conversioim of ketogulonic acid to ascorbic acid, Vitamin C (23). As a result, both the imunman and time guinea Jig nmust be supplied witim Vitamin C in timeir (liet to avoid the development of scurvy. Scurvy can, timerefore, be regarded as a metabolic disease simared by time entire imumaim race which is kept in remission by time adequate intake of Vitamiim C. Such a consideration provides the key to one of the therapeutic approaches used in treatment of metabolic diseases: some individuals with metabolic disorders will have unusual imutritiommal requirenments for nmaintenance of health that are differeimt from that of the general population. Histidenemia lim some cases, the biochemical aimd clinical features of disease are the result of the accumulation of a compound that is a remote precursor of the blocked reaction. Timis occurs particularly if the reaction preceding time block is freely reversible. The accumulation of liver glycogen in excessive amounts in Type I glycogeim storage disease that we have already mentioned is aim exanmple of such an accumulation. Tn still other disorders there will be ties of a substance which normally is accumulation of pimeimylpyruvic acid aiid the patieiits with phenylketonuria is an production of increased quantipresent in small amounts. The pimenylacetic acid in the urine of example of the way in which a Vol. 14, No. 7, 1967 HUMAN HEREDITARY DISEASES 561 basic biochemical abnormality results iii a metabolic diversion. Another example is histidinemia, a disorder of’ amino acid! metabolism for which the enzyme defect was first demonstrated by i)r. Lai)u et al. (24). Time chemical abnormality for this disorder was detected as a result of a positive ferric chloride test for phenylketonuria found ill the urine of a child attending a speech clinic. Unlike most patients with pheiiylketonuria, this child was of normal intelligence and had a normal concentratioim of phemmylalanine in her plasma. The diagnosis of imistidinernia was proven when it was demonstrated that imidazole pyruvic acid derived from histidimme was time substance responsible for the positive fem’ric chloride test. Increased quantities of histidine were also present in plasma and urine of both this girl and her younger brother. The abseimce of the enzyme, histidase, was demoimstrated readily by use of hardened skin removed from aroummd the edge of the nail with fimmgernail clippers. Such cornified epithelium from normal individuals contains a measurable amount of the enzyme histidase which breaks down histidine to urocanic acid; there was nomme demonstrated in samples obtained from these children. At the present time there have been at least 15 cases of histideimemia identified. All but 2 of these patients are repoi’ted to have al)mmormalities of speech amid some have mental retardation (i). The way iii wimich an enzyme defect could result in a specific disorder of speech opens miew realms iim the understanding of time role of biochemical processes iim brain function. Our speech experts believe that timese patients to learn by their have a simoi’tened auditory niemory and so are uimable selise of hearing as effectively as cami normal iimdivid- uals. Yet the intelligence of our two patients amid by the visual route is entirely miormal. Since the been identified iii individuals over 13 years of age, of this disorder that might develop in adult life are their ability to learn disorder has not yet the cliiiical features not known. Brain Function Abnormalities In recent years, we have become aware of an increasing number of specific defects of metabolism that are associated with abnormalities of brain function. One of tlmese is known as branched-chain ketonuria or Maple Syrup Urine i)isease. This was first described in 1954 in a family in whom 4 of the 6 children had died within the first few weeks of life from severe brain damage (2S). The mother brought to the attention of the doctors the fact that the urilme of the affecte(l children had a characteristic odor similar to that of maple syrup. On the basis of this ol)servation, the urine was examined iii greater detail ammdan abnormal concentration of organic acids was detected which were eventually found to be the keto acids derived from time branched-chain amino acids 562 SEEGMILLER Clinical Chemistry leuciiie, valine, amid isoleucine, whelm accumulate as a result of a deficiency of time decarhoxylase that normiiahly degrades theni (1). The severe brain damage in such instances can be prevented by treatment with a syntimetic diet low iii branched-chain amino acids. This (hisease was (liagimosed in a baby S thays old; the special diet was begun immediately and has been colitillued ever since (26). The child is now 5 years of age, has growil well, and has a iiornmal intelligence. Other patients with this disorder lmave 1)een similarly treated (1). Ammotlmer imiherited biocimemical disorder which gives rise to neurologic symptoms was first described nearly three years ago (27). The patieimts, two young brothers, had spasticitv, choreoatlmetosis, mental retardatiomm, and a most bizarre behavior which consisted of a conmpulsive bitilig resimiting in the ends of time fingers and the lips being chewed away. It \5 associated with hyperuricernia and with the lamgest 1)roduCtioll of uric acid i)(r kilogram of body weighmt that has yet been found. The developmacnt of gouty arthritis imas been a relatively late manifestation of the disease. However, gouty nephropathy has contributed to the death of other patients by the age of puberty (28). rhllie disorder affects only nmales an(l simows a pattermi of inheritance carrie(1 by the fenmales over at least 3 generations, thereby suggesting that the gene controlling the biochemical defect resides on the X chromosome (29). The recent discovery that these children are lacking ammenzyme of purine metabolism (hypoxantimine-guanine pimosphmoril)osyltraiisferase) provides evidence that function of this enzyme is involved iim the normal regulation of purine biosyiithesis (30). in additiomm, it provides a biochemical basis for not only aiiotlmei’ type of iteurologic disease but also a link betweemm a characteristic abnormality of behavior and a genetically determined biochemical (hsorder. Time precise mechanism by which a single genetic defect gives rise to this clinical syndrome can provide a powerful wedge in our search for knowledge that might be used in more effectively controlling such disorders. Summary Modern genetics aiid biochemistry provide new insight into some old and new imereditary diseases which in turim enlarge the future possibilities for recognition and treatnient of these thsorders. There is a great potential value of mammalian mutants-these experiments of natureas tools for extending our knowledge of the importance of specific biochemical reactions in the normal physiology arid biochemistry of the imuman. Time immediate future holds the prospect that an even larger number of genetically controlled individual chemical differences will be recognized in the human species. This should result from the Vol. 14, No. 7, 1967 HUMAN HEREDITARY. DISEASES 563 performance of a larger number of routimie clmemical determinations on an increasing segment of the patient populatiomm made possible by the widespread use of automated analytic equipment in clinical laboratories. References 1. Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S. The Metabolic Basis of Inherited Disease (ed. 2). McGraw-Hill, New York, 1966. 2. Garrod, A. E., The Croonian Lectures on Inborn Errors of Metabolism. Lecture II. Aikaptonuria. Lancet 2, 73 (1908). 3. Beadle, G. W., and Tatum, E. L., Genetic control of biochemical reactions in Neurospora. Proc. Nafl. Acad. .Sci. U. S. 27, 499 (1941). 4. Beadle, G. W., Genes and chemical reactions in Nenrospora. Science 129, 1715 (1959). 5. Horowitz, N. H., and Leupold, F., Sonic recent studies bearing on the one gene one enzyme hypothesis. Cold Spring Harbor Symp. Quant. Biol. 16, 65 (1951). 6. Benzer, S., “The Elementary Fnits of Heredity.” Iii The Chemical Basis of Heredity, McElroy, W. D., and Glass, B., Eds. Johns Hopkins Press, Baltimore, 1957, p. 70. 7. Pauling, L., Itano, H. A., Singer, S. J., and Wells, I. C., Sickle cell anemia, a molecular disease. Science 110, 543 (1949). 8. Ingram, V. M., Gene mutations in hunian haeinogiobin: The chemical difference between normal and sickle cell haemoglobin. Nature 180, 326 (1957). 9. Nirenberg, M., Caskey, T., Marshall, H., Brinincombe, H., Kellogg, D., Doctor, B., Hatfield, I)., Levin, J., Rottman, F., Pestka, S., Wilcox, M., and Anderson, F., The RNA code and protein synthesis. Cold Sprinq Harbor Synp. Quant. Biol. 31, 11 (1966). 10. Jacob, F., and Monod, J., Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318 (1961). 1. Yanofsky, C., Amino acid replacements associated with mutation and reeombination in the A gene and their relationship to iii vitro coding data. Cold Spring harbor Si/nip. Quant. Biol. 28, 581 (1963). 12. Ames, B. N., and Hartman, P. E., The iiistidimie operon. Cold Sprin#{231}j Harbor 8pm p. Quant. Biol. 28, 349 (1963). 13. FoIling, A. t)ber Aussclieidung von Plicnylbrenztraiibcnsiiure in den Ham als Stoffwechselanomnalie in Verbindung mit Imnbezillitiit. ItoppeScylers Z. Piiysiol. Chem. 227, 169 (1934). 14. LaDu, B. N., Zammnoimi, V. G., Laster, L., and Seegnmiller, ,T. E., The nature of the defect in tyrosiae metabolism in aicaptonuria. J. Biol. Chem. 230, 251 (1958). 15. Taniguchi, K., and Giessing, L. B., Studies on tyrosinosis. TI. The activity of the transaminase, parahydroxyphenyl-pyruvate ovidase and liomogemitisic-acid oxidase. Brit. Med. J. 1, 968 (1965). 16. Halvorsen, S., and Gjessing, L. H., Studies au tyrosinosis. I. Effect of low-tyrosiuue and low phenylalanine diet. Brit. Mcd. J. 2, 1171 (1964). 17. Halvorsen, S., Dietary treatment of tyrosinosis. A in. ,J 1)iseases Children 113, 38 (1967). 18. Seegmiller, J. E., The acute attack of gouty arthritis. Arthritis Rheuniat. 8, 714 (1965). 19. Seegmnilier, J. E., Laster, L., and Howell, H. H., Biochemistry of uric acid and its relation to gout. New Engi. J. Med. 268, 712, 764, and 821 (1963). 20. Con, G. T., and (‘on, C. F., Glucose-6-phosphatase of the liver iii glycogen storage disease. J. Biol. Chem. 199, 661 (1952). 21. Fine, H. N., Strauss, J., and Donaell, C. N., Hyperuricemia in glycogen-storage disease type I. Am. J. Diseases Children 112, 572 (1966). 22. 23. 24. 25. Alepa, F. P., Howell, B. tween glycogen storage Burns, .1. J., Missing step m.-ascorl,ie acid. Nat nrc B., Klinenberg, J. B., and St’eguuuiller, J. H., Relationships disease and tophaeeous gout. Am. J. .1! ed. 42, 58 (1967). in maim, monkey and guinea pig required for the liiosyntluesis 180, 553 (1957). be. of LaDu, B. N., Howell, H. H., Jaeoby, C .A., St’egnuiller, .J. H., Sober, H. K., Zanuuoni, V. C., (‘anliy, .1. P., and Ziegler, L. K., Clinical and biochemical studies au two eases of histidinemia. Pediatrics 32, 216 (1963). Menkes, J. H., Hurst, P. L., and Craig, J. M., New syndrome: Progressive familial in- 564 2(i. 27. 28. 29. 3U. EEGMILLER Clinical Chemistri, fantile cerebral tlysfunctioii associated with unusual urinary substance. Pediatrics 14, 462 (1954). Westall, Ii. C., [)ietary treatment of a child with maple syrup urine ilisease (brauuched chain ketoacidunia). Arch. Disease Childhood 38, 485 (1963). Leselu, M ., and Nyhiamu, W. L., A fain i lint disorder of uric acid uncta I olisuui nuid central nervous system function. Am. J. Med. 36, 561 (1964). Sass, J. K., Itabashi, H. H., and I)exter, H .A., .Juveuuile gout with brain involvement. Arch. Neurol. 13, 639 (1965). Shapiro, S. L., Sheppard, G. L., Jr., 1)reyfuss, F. H., and Newcoinbe, D. S., X-linked recessive inheritance of a syndronme of mental retardatious with hyperunieemia (31204). Proc. Soc. Exptl. Biol. Med. 122, 609 (1966). Scegni!ler, .1. E., Hosenblooni, F. hi., and Kelley, W.N., Au euizyuume defect assoeuate(l with a scx-liuiked human neurological disorder and excessive punine synthesis. Science. 155, 1682 (1967).