Cheinistry 02 :`4cntal Disease Aildress by Lii1uS Pauling University of California School of Medicine, 8:00 P.R. Tuesday 13 February 1962 There are many kinds of mental disease, and nany chemical aspects of mental disease. The human body, including the brain : >Thich is the organ of thinking and memory, is composed of molecules. v2cto:-s of disease are molecules or are composed of molecules. The genes seem to be molecules of deoxyribonucleic acid. The impact of the environment on a human being is by siay of molecules A of che?r&cel substances . m Chemicals, called drugs, are used for the treatment 2nd control of xental disease. I shall not discuss the entire subject, chemistry and mental disease, for several reasons. First; I do not have time to do justice to the whole subject. Second, I do not kno>; enough about the n ature of the intermolecular Jjh&%iApcB~-~% interactions between the many valu,able drugs, such as chlorpromazine, now A being used in the trea-tment and control of mental disease to present a sound and reasonable discussion of the mechanism of their action; I'm not sure that anybody kno~~enough. I shall accordingly not devote any time to this subject. 3 -L- Some of the many types of mental disorder result from birth injury or enviro3mental causes of a macroscopic character, l*Thich cannot be described as Temporary or permanent ~Z&R impairment of brain function may also result from ingestion of substances not normally present or normally present only in small amounts in the body. AIllOng such substances are ethanol, compounds of heavy metals dK"rnad as a hatter"), and organic substances found in plants, such as LSD (Ijrsergic acid diethylamide) and mescaline. Chromosomal abnormalities, such as those resulting from nondisjunction, are a common cause of mental deficiency, and may possibly be involved in some cases of mental illness. Examples are Mongolism (extra chromosome numbers, or other disease (Xxy, XXXY, XXXXY). births, that of Turner's disease about o3e in 300, and that of Klinefeltek disease about one in 400. 4 The abne :Fe manufacture twice as many molecules of the corresponding enzyme as one gene. There may be exceptions, however. There is some evidence -that the enzyr.les manufactures by the genes of the X chromosome are not present in twice the -- -3- mount in tromen as in i!lell, and some evidence -th.at one X chromosome in the cell remains extended, with its genes presuxa'bly active, :rhereas the other one (or more th.>n one) rolls up, in such a day as to cut down on the gene activity. ,Thi.s rolled-up chromosome is pres*um&oly responsible for the Barr test. Probably the major cause of both mental deficiency and mental illness is gene mutation. It is usually estimated that aboxt half of congenital defects ir, infants are of genetic origi;?. An abnormal gene nay fail to manufacture the molecules of enzyme for r:;hich the allelomorphic normal gene is responsible, or ma> ;nanuPacture abnor- :XLL inolecules that are deficient in enzyme activity. The most thoroughly investigated w of this sor'; is phenylketonuria. h The enzyme involved, loca-ted in the liver, catalyzes the oxida%:on of phenylzlanine to tyirosine. Phenylke-torxxria l?as discovered by F$lling in Bor~ay in l?$.. It is trans- mitted by an autosoAmal recessive gene. The inciderxe in Europe and UC-Led States is one in Co for carriers. About one percent of institutFonallzed defectives are phenylketonix+ics. Tizeir mental defect is severe, T;,ri-!;h &) De-.--- i - cent of the patients having IQ, less tha-r- 40. Neurolo@cal disturbances i,xlude an abnormal encephslograx, o:Xen ltith eplleptiform seizures, cl by-per c-t Ivit y , 1, - i. - poor attention span, and ilOTX%i behavior. There are few men-tal diseases that are as well understood as phenyl- ketoaxLn. The cause of most mental disorders is unknot, and xany are :r?ot well-defined, even fro:1 the clinical standpoint. It is p:-obable that the zental deterioration that occurs in later life in patients with Hunti~gdon's C! is the result of R change in brain chemistry, the nature of TThich is -6Q-47 not 1;no-m at present. The deposition of copper inkpatient: wi-th kYlson's A - disease is without doubt responsible for the mental as Ire11 as R hysical jllani- festations of the disease. A change in brain chemistry xay well be responsible also fey schizophrenia a-nd other form of mental illness. Despite the present lack of knowledge, the possibil<.ty that rmny ::ceiltd the hope th:zt of xentnl disease has been carried on for five years, at first T.riC,h Dr. Xi-ha&~ iippxan as the principal i.nvesti@ator, and Flore recently by Dr. Kenneth X. F. 72, Shaw, Dr. 2!cm Perry, ;md their collaborators. lfiLssociatcd T,ri.th this vo:!: ha.2 been a study of mental deficiency in Hawaii, carried out lnrgely by Dr. Elmira Goettsch. This work has ~O'CT bee:? transferred to the diversity of Hawaii, wjt;l the President, Laurence Snyder, as the responsible investigator. The xorl; in the Califo~~~ia Institute of Technology has been quite varied in nature. As e-9 exaxplc of what has bee;1 and is being done, I may nen-tion briefly the studies by Dr. Shaw and his collaborators on Hsrtmp disease. This disease was firs-t described by Dent and his col.rorkezs in England in 195s 4 Four our of eight childzen in the original Hartnup cases in nine fmilies have now been found, in England, Hollmd, and Gemany. The paxents in three families are blood relations. The ,nanifestations of the disease include a red scaly skin rash, sensi- tivity of the skin to sxmlight, intermittent cerebellar ctaxia that imolvcs a lurching walk, jerky arx xovemext, and &+tensioh t:re:nor. The mental state ranges from cormalto retarded and may include mid emotionai in&ability, psychosis, delirium, alusions, and hallucinations. Tlese features are variable and episodic, and can be precipitated by infection or psychological stress. A cons'tant bioche::lical finding is a large excretion 0P certain amino acids. Dr. Shm obtained several 11artnup urine specil:lens from Dent's laboratory- in ix0 years ago. Many amino acids are excreted - 3,mounts ten times greater c - .) - than normal, but others alne not affected. The amino eciduria is csused by defective reabsorption in the renal tubule. Professor Dent had reported an abnormal metabolism of indole compounds, but Dr. Shaw found no such abnormality. He was then successful in resolving this contradiction, by coll&orative work with Professor Dent, in whi.ch a boy in the Zartnup fsmily and a normal individual were given two grams of L-tryptophcn by mouth, at first Trithou-t and then Ttith the antibiotic neomycin, also given by mouth, to prevent the growth of intestinal microorganisms. Slide 1. chromatog~~am Slide 2. Chromatogrom c of amino acids in Hnrtnup urine (only half as much urine used). Note the great amountsof some .amino acids. of alin acid.q in normal urine. Slide j. (13). Urinary indole after ingestion of tryptophan, both normal and Hartnup. The Hartnup urine contains much larger amounts of . several indoles than the normal urine. Slide 4. (16). The same, except - that the antibFotic neomycin was given. Both subJects were also placed on a diet containing no plant materials in order to exclude exogenous indoles. It is seen that the excretion of indolc compounds by the Hartnup patient was essentially noznal. Apparently the Hartnup abnorzC!.ity involves an ?. mpaired permeability of the intestinal wall as >iell as of the renal tubule. This means that tryptophan and other m~tino acids from food remain longer in the intestine for metaboli,sm b-7 bacteria 3 7 converting them into indole compounds. The impaired permeability of tissues in Hartnup disease may cause many chemical abnormalities--variable deficiency of tryptophan, partial deficiency -tPM nicotinamide pip other essential agents, possible toxic effects of metabolites produced by intestinal bacteria. The treatment of Hazztnup disease is siimple--administration of a high protein diet and also nicotinamide. Possibly suppression of the gro-crth of intestinal microorganfsms by the use of neomycin tiould result in improvement. -8- The molecular diseases that lead to mental deficiency or mental illness have not been investigated lar abnormality, The most thorough stud$es respect to the nature of the molecu- - d - that have been carried out of molecular diseases are those of the hemoglobinemias, including sickle-cell r anemia, and I shall present now a discussion of the present state of knowledge about these molecular diseases. One of the striking feat gene is its high inci- dence in certain populations. In some malarial regions in Africa as many as fifty percent of the people are sickle-cell heterozygotes. The nature of the abnormality that causes its high incidence is now known, It is protection against malaria. It is seen that there is a close relation between molecular disease and evolution, H . ~\lOu9Tl QA9 - Life is a relationship among molecules, not a property of any one molecule, So is therefore disease, which endangers life, :