Curse Blessing Ghetto - Lecture Notes 1

Curse and Blessing of the Ghetto Tay-Sachs disease 1s а choosy killer, one that for centuries targeted Eastern European Jews above all others. Ву decodlng its lethal logic, we сап Jearn а Jot about how genetic diseases evolve- and how they сап Ье conquered. м JARED DIAMOND arie and I hated her at first sight, even though she was r.rying hard to Ье helpful. As our obstetrician's genetics counselor, she was just doing her job, ex­ plaining to us the unpleasant results that might соте out of the generic tests we were about to have perfoпned. As а scientist. though. 1 already k.new all I wanted to know аЬоU\ Tay-Sachs disease, and I didn't need to Ье rem.inded that the ЬаЬу sen­ tenced to death Ьу it could Ье my own. Foitunately, the tests would reveal that my wife and I were not carriers of the Tay-Sachs gene, and our preparenthood fears on that matter at least could Ье put to rest. But at the time 1 didn't yet k.now that. As ! glared angrily at that poor genetics counselor, so strong was my anxiety that now, four years later, 1 сап still clearly rememЬer what was going througb my m.ind: If I were an evil deity, J thought. trying 10 devise exquisite tor­ \Ures for babies and their parents, 1 woold Ье proud to have de­ signed Tay-Sachs d.isease. Tay-Sachs is completely incuraЫe, unpreventaЫe. and pre­ prograrnmed in the genes. А Tay-Sachs infant usually appears nonnal for the first few months after Ьiith, just long enough for the parents to grow to love him. An exaggerated "startle reac­ tion" to sounds is the first orninous sign . At aЬout six months the ЬаЬу staJts to lose control of his head and can't roll over or sit without support. Later he Ьegins to drool, Ьreaks out into un­ motivated Ьouts of laughter, and suffers convulsions. Then his head grows abnormally large, and he Ьecomes Ыind. Perhaps what's most frightening for the parents is thar rheir ЬаЬу \oses all contact with his environment and Ьecomes viJtually а vege­ taЫe. Ву the child's third ЬiJthday, if he's sti\1 alive, his skin will \Um yellow and his hands pudgy. Most likely hc will die Ьc­ fore he's four years old. Му wife and I were tested for the Tay-Sachs gene Ьccause at the time we rated as high-risk candidates, for two reasons. Firs� Marie was carrying twins, so we had douЬ\e the usual chance to bear а Tay-Sachs ЬаЬу. Second, Ьoth shc and I are of Eastem European Jewish ancestry, thc population wirh Ьу far the world's highest Tay-Sachs frequency. ln peoples around the world Tay-Sachs appears once in ev­ ery 400,000 ЬiJths. But it appears а hundred times more fre­ quenlly-ahout once in 3,600 Ьiiths-among descendants of Eastem European Jews, people known as Ashkenazim. For de• scendants of mosr Olher groups of Jews--Oriental Jews, chiefly from the Middle East, or Sephardic Jews, from Spain and other Mediterranean countries-the frequency of Tay-Sachs disease is no higher 1han in non-Jews. Faced with such а clear correla­ tion. one cannot help but wonder: What is it abour this one group of people that produces such an extraordinarily high risk of this disease? Finding the answer to this question concerns all of us, re­ gardless of our ancestry. Every human population is especially susceptiЫe 10 ceitain diьeases, no! only Ьecause of its life-sty\e bur also Ьecause of its generic inherirance. For example, genes pur European whites at higb risk for cystic fibrosis, African Ыacts for sickle-cell disease, Pacilic lslanders for diaЬetes­ and Eastem European Jews for ten different diseases, inc\uding Tay-Sachs. It's not th at Jews are поrаЫу suscepliЬ\e to generic diseases in general; but а comЬinarion of hisiorical facrors has led to Jews' Ьeing intensively studied, and so their susceptiЬili­ ties are far Ьetter known than those of, say, Pacific lslanders. Tay-Sachs exemplifies how we сап deal with such diseases; it has Ьееп the oЬjcct of the most successful screening prograrn to date. Moreover, Tay-Sachs is helping us understand how ethnic diseases evolve. Within the past c ouple of years discoveries Ьу molccular Ьiologjsts have provided tantalizing c\ues ro precisely how а deadly gene can persist and spread over the cenruries. Tay­ Sachs may Ье primarily а disease of Eastem European Jews, Ьut through this affliction of опе group of people, we gain а window оп how our genes simultaneously curse and Ыess us а\1. The disease's hyphenated пате comes from the two physi­ cians-British ophthalmologist W. Тау and New York neurol­ ogist В. Sachs-who independently fust rccognized the disease, in 1881 and 1887, respectively. Ву 1896 Sachs had seen enough cases to rea1ize that the disease was most common among Jewish children. ANNUAL EDITIONS Not until 1962, however, were researchers аЫе to trace the cause of the affliction to а single biochemicaJ abnorma!ity: the excessive accumulation in nerve cel ls of а fatty substance called Gм 2 ganglioside. Normally Gм2 ganglioside is present at only modest levels in cell membranes, Ьecause it is constantly being broken down as well as synthesized. The breakdown depends on the enzyme hexosaminidase А, which is found in the tiny struc• rures within our cells known as lysosomes. !n the unforrunate Tay-Sachs victims this enzyme is laclung, and without it the gan­ glioside piles up and produces all the sympюms of the disease. We have two copies of the gene that programs our supply of hex osami nidase А , one inherited from our father. the other from our mother; each of our parents, in tum . has two copies derived from their own parents. As long as we have one good сору of the gene, we can produce enough hexosaminidase А to prevent а buildup of Gм2 gang!ioside and we won ' t get Tay-Sachs. This genetic disease is of the son termed recessive rather than dominant-meaning that to get it. а child must in­ herit а defecti ve gene not just from опе parent but from Ьoth of them. Clearly. each parent must have had one good сору of the gene along with the defective copy-if either had had two defective genes. he or she would have died of the disease long before reaching the age of reproduction. In genetic terms the diseased child is bomozygous for the defective gene and both parents are heterozygous for it. None of this yet gives апу hint as to why the Tay-Sachs gene should Ье most common among Eastern European Jews. То соте to grips with that question, we must take а shon detour into history. From their ЬiЫical home of ancient Jsrael, Jews spread peacefully ю other Mediterranean lands, Yemen, and lndia. They were also dispersed violently through conquest Ьу Assyr­ ians, Babylonians, and Romans. Under the Carolingian k.ings of the eighth and ninth centtiries Jews were invited 10 settle in France and Gerrnany as traders and financiers. Jn subsequent centuries, however, perseculions triggered Ьу lhe Crusades gradual ly drove Jews oul of Westem Europe; the process culmi• nated in their total expulsion from Spain in 1492. Tlюse Spanish Jews-<:alled Sepharctim-fled to other lands around the Med­ iterranean. Jews of France and Gerrnany-the Ashkenazim­ fled east to Poland and from there 10 Lithuania and westem Rus­ sia, where they setUed mostly i n towns, as businessmen en­ gaged in whatever pursuit they were allowed. There the Jews stayed for centuries, through periods of both tolerance and oppression. But toward the end of the nineteenth century and the beginning of the twentieth, waves of murderous anti-Semitic attacks drove millions of Jews out of Eastem Eu­ rope. with most of them heading for the United States. Му mother's parents, for exarnple, fJed 10 New York from Lithuanian pogroms of the 1 880s, while ту father' s parents fled from the Ukrai nian pogroms of 1 903-6. The more modem history of Jew­ ish migration is рrоЬаЫу well known to you all: most Jews who remai ned in E.astem Europe were exterminated during World War II, whiJe most the survivors immigrated to the United States and lsrael. Of the I З mi llion Jews alive today, more than three­ quarters are Ashkenazim, the descendants of the Eastem Euro­ pean Jews and the peop le most at risk for Tay-Sachs. Have these Jews maintained their genetic distinctness through the thousands of years of wandering? Some scholars claim that there has Ьееn so much intermarriage and conversion that Ashkenazic Jews are now j ust Eastem Europeans who adopted Jewish culture. However, modem genetic studies refute that speculation. First of all, there are those len genetic diseases that the Ash­ kenazim have somehow acquired, Ьу which they differ Ьoth from other Jews and from Eastem European non-Jews. !n addi­ tion. many Ashkenazic genes tum out to Ье ones typical of Pal­ estinian AraЬs and other peoples of the Eastem Mediterranean areas where Jews originated. (ln fact. Ьу genetic standards the current Arab-lsraeli conflict is an intemecine civil war.) Other Ashkenazic genes have indeed diverged from Mediterranean ones (iocluding genes of Sephardic and Oriental Jews) and have evolved to converge on genes of Eastem European non-Jews subject to the same local forces of narural selection. But the de­ gree to which Ashkenazim prove to differ genetically from Eastem European non-Jews implies an intermarriage rate of only aЬout 1 5 percent. Can history help explain why the Tay-Sachs gene in panicu­ lar is so much more common in Ashkenazim than in their nC>n• Jewish neighЬors or in other Jews? At the risk of spoiling а mys­ tery, I'll tel1 you now that the answer is yes, but 10 appreciate it, уоu·н have to understand the four possiЫe explanations for the persistence of the Tay-Sachs gene. Fi rs� new copies of the gene might Ье arising Ьу mutalion as fast as existing copies disappear with the death of Tay-Sachs children. Tha1·s the most likely explanation for the gene's per­ sistence in most of the world, where the disease frequency is only one in 400,О<Ю Ьinhs--that frequency reflects а typical hu­ man mutation rate. But for this explanation 10 apply ю the Ash• kenazim would require а mutation rate of at Jeast.one per 3,600 binhs-far аЬоvе the frequency observed for·•ny human gene. Furthermore, there would Ье по precedent for one panicular gene mutating so much more often in one human population than in others. As а second possibllity, the Ashkenazim might have ас• quired the Tay-Sachs gene from some other people who already had the gene at high frequency. Arthur Koestler's controversial Ьооk The Thirteenth Tribe, for example, popularized the view that the Ashkenazim are really not а Semitic people but are in­ stead descended from the Khazar, а Turkic triЬe whose rulers converted to Judaism in the eighth century. Could the КЬаzаr havc brought the Tay-Sachs gene to Eastem Europe? This spec­ ulation makes good romantic reading, but there is no good evi­ dence to suppon it. Moreover, it fails to explain why deaths of Tay-Sachs children didn' t eliminate the gene Ьу natural selec­ tion in the past 1 ,200 years, nor how the Khazar acquired high frequencies of the gene in the first place. The third hypothesis was the one preferred Ьу а good many geneticists until recently. lt invokes two genetic processes. lermed the founder effect and genetic drift, that may operatc in small populations. То understand these concepts, imagine that 1 00 couples settle in а new land and found а population that then increases. Jmagine further that one parent among those original 100 couples happens 10 havc some rare gene, опе, say, Cu rse and Blesslng of the Ghetto that nomially occurs at а frequency of one in а million. Тhе gene's frequency in the new population wi\l now Ье one in 200 as а result of the accidental presence of that rare founder. Or suppose again that 100 couples found а population, but that one of the 1 00 men happens to have lots of kids Ьу his wife or that he is exceptionally popular with other women, while the other 99 men are childless or have few k.ids or are simply less popular. Тhat one man may thereby father I О percent rather than а more represen1a1ive one percent of the next genera1ion' s bables, and their genes will disproponiona1ely reflec1 1hat man's genes. In other words, gene frequencies will have drifted Ьetween lhe first and second generation. Тhrough these two types of genetic accidents а rare gene may occur with an unusuaJly high frequency in а small expand­ ing population. Eventually, ifthe gene is harrnful, natural selec­ tion will bring its frequency back to nomial Ьу killing off gene bearers. But if the resultant disease is recessive-if heterozy­ gous individuals don't get the disease and only the rare, ho­ mozygous individuaJs die of it-1he gene' s high frequency may persist for many generations. These accidents do in fact accounl for the astonishingly high Tay-Sachs gene frequency found in one group of Pennsylvania Dulch: out of lhe 333 people in this group, 98 proved to carry the Tay-Sachs gene. Those 333 are all descended from one cou­ ple who settled in the United States in the eighteenth century and had 1 3 children. Clearly, one of that founding couple must have carried the gene. А similar accident may explain why Tay­ Sachs is also relatively comrnon among French Canadians, who number 5 million loday but are descended from fewer than 6,000 French imrnigrants who arrived in the New World Ьe­ tween 1 638 and 1 759. In the 1wo or three centuries since both these founding events, the high Tay-Sachs gene frequency among Pennsylvania Dutch and French Canadians has nol yet had enough time to decline ю nomial levels. The same mechanisms were one proposed to explain the high ra1e of Tay-Sachs disease arnong the Ashkenazim. Per­ haps, lhe reasoning wenl, the gene just happened 10 Ье overrep­ resented in the founding Jewish population that se11led in Gemiany or Eas1em Europe. Perhaps the gene j ust happened 10 drift up in frequency in 1he Jewish populations scattered arnong the isolated towns of Eastem Europe. lt,see·;;,�-�nllkelyti;;1g-;,;t1�"';��f;-u wou ld have pumped up the frequency of the same gene not once but twlce ln the same populatlon. Bul geneticists have long questioned whether the Ashkena­ zim population's hislory was real\y suitaЬie for these genetic accidenls to have been significant. Remember, the founder ef­ fect and genetic drift Ьесоmе significanl only in smal\ populu­ tions, and the foundi ng populations of Ashkenazim may have been q uite large. Moreover, Ashkenazic communities were con­ sidcraЫy widespread ; drift would have sent gene frequencies up in some юwns but down in others . And. finally, natural se­ lec1ion has Ьу now had а thousand years 10 restore gene fre­ quencies to norrnal . Granled, those doubts are based оп hisюrical dala. which are not always as precise or reliaЫe as one mighl wanl. But within the pas1 several years the case againsl those accidental explana­ tions for Tay-Sachs disease in lhe Ashkenazim has been Ьol­ s1ered Ьу discoveries Ьу mo\ecular Ьiologists. Like all pro1eins, lhe enzyme absent in Tay-Sachs children is coded for Ьу а piece of our DNA. Along that panicular stretch of DNA there are thousands of differen1 si1es where а muta1ion could occur 1hat would resull in no enzyme and hence in the same se1 of symptoms. If molecular Ьiologists had discovered tllat aU cases of Tay-Sachs in Ashkenazim involved damage ю DNA at the same site, lhat would ha ve been strong evidence thal in Ashkenazim the disease slems from а single mu1a1ion that has been mulliplied Ьу the founder effect or genelic drifl-in other words, the high incidence of Tay-Sachs among Eastern Euro­ pean Jews is accidental. ln reali1y, though, several different юutations aiong this slretch of DNA have been idenlified in Ashkenaziю, and 1wo of them occur much more frequently than in non-Ashkenazim populations. 11 seems un\ikely 1Ьа1 genetic accidents would have pumped up the frequency of the sarne gene not once bu1 twice in the same population. And 1ha1's по1 the sole unlikely coincidence arguing against accidental explanations. ·Recall that Tay-Sachs is caused Ьу the excessi ve accumula1ion of one fa1ty substance, Gм2 ganglio­ side, from а defect in one enzyme, hexosaminidase А. But Tay­ Sachs is one of len genelic diseases charac1eristic of Ashkena­ zim. Among those other nine, two-Gaucher' s disease and Ni­ emann-Pick disease-result from the accuюulation of two other fatty substances similar to Gм2 ganglioside, as а result of de­ fects in lwo olher enzymes similar to hexosaminidase А. Yet our bodies contain thousands of different enzymes. lt would have Ьееn an incrediЫe roll of the genetic dice if, Ьу nothing more 1han chancc, Ashkenazim had independently acquired muta1ions in 1hree closely related enzymes-and had acquired murations in опе of those enzymes twice. AII these facts bring us 10 the fourth possiЬ\e explanation of why the Tay-Sachs gene is so prevalenl among Ashkenazim: namely, 1ha1 somelhing about them favored accumulation of Gм2 ganglioside and re\a1ed fats. For comparison, suppose lhat а friend douЬles her money оп one slock whi le you are getting wiped oul wilh your invest­ ments. Taken alone, that could jusl mean she was lucky оп lhat one occasion. Bu1 suppose that she douЫes her money оп each of two differenl s1ocks and at the same lime rings up Ьig profils in real estate while also making а killing in Ьonds. That i mplies more than lady luck; il suggests that something about your friend-like shrewd judgment-favors financial success. What could Ье the Ыessings of fat accumulation in Eastern European Jews? AI firs1 lhis question sounds wcird. Afler aJI, that fat accumulation was noticed only because of the curses it Ьestows: Tay-Sachs, Gaucher's. or Niemann-Pick disease. Bu1 many of our common genetic di seases may persist Ьecause they bring both Ыessi ngs and curscs (see "The Cruel Logic of Our ANNUAL EDITIONS Genes," Discover, NovemЬer 1 989). Тhеу kill or impair indi­ viduals who inheril two copies of the fau!ly gепе, but 1hey help lhose who receive only one defec1ive gene Ьу pro1ee1ing 1hem againSI 01her diseases . The ЬeSI underslood example is lhe sickle-ccll gene of African Ыaclcs, which oflen kills homozy­ go1es bul pro1ec1s helerozygotes agai ns1 malaria. Na1ural selec­ tion susta1ns such gcnes bccause nюre hete:roz.ygotes than nom1al individuals survive to pass on their genes. and those ex­ tra gene copies offset the copies lost through 1he deaths of ho­ mozygo1es. So let us refine our queslion and ask, Whal Ыessing could the Tay-Sachs gene bring lo those individuals who are heterozy­ gous for it? А clue first emerged back in 1 972. with the puЫi­ cation of 1he results of а questionnшre that had asked U .S. Ashkenzaic parents of Tay-Sachs children what their own East­ ern European-bom paren1s had died of. Кеер in mind that since these unforrunale children had 1О Ье homozygotes, with two copies of the Tay-Sachs gene, all their parents had 10 Ье het­ erozygotes, with one сору. and half of thc parcnts' parents a\so had to Ье heterozygotes. As it iumed oul, most of lhose Tay-Sachs grandparents had died of the usual causes: heart disease, stroke, cancer, and dia­ Ьetes. B u1 Slrikingly, only one of the 306 grandparenls had died of tuherculosis, even lhough ТВ was generally one of the Ьig killers in these grandparents' time. Indeed, among the general population of large Eastern European cities in tl1e early twenti­ eth century, ТВ caused up to 20 percent of all deaths. This Ьig discrepancy suggested that Tay-Sachs heterozy­ gotes might somehow have been protected againSI ТВ . Interest­ ingly, it was already weU known that Asbkenazim in general had some such protection: even when Jews and non-Jews were compared within the same European ci1y, class, and occupa­ tional group (for example, Warsaw garment workers), Jews had only half the ТВ dealh rale of non-Jews, despite thcir Ьeing equally susceptiЬle to infection. Perhaps, one could reason, the Tay-Sachs gеле fumished part of that we!l-estaЫished Jewish resistance. We're not а meltlng pot, and we won't Ье for а long tlme. Each ethnlc group has some characteristlc genes of its own, а legacy of lts dlstlnct hlstory. А second clue to а helerozygote advantage conveyed Ьу the Tay-Sachs gene emerged i n 1 983, with а fresh look at the data conccmi ng lhe distributions of ТВ and thc Tay-Sachs gеле wi1hin Europe. The statistics showed that thc Tay-Sachs gene was nearly three ti me.s more frequent among Jews originating from Austria, Hungary, and Czechoslovakia-arcas ,vhere an amazing 9 to I О percent of the population wcrc heterozy­ gotes-th,ш among Jews from Poland, Russia. and Germany. At 1he �ame ti inc rccords from an old Jewish ТВ san,нoriurn in Denver i n 1 904 showed that among pa1ients born i n Europe belween 1 860 and 1 9 1 О. Jews from Austria and Hungary werc overrepresented. !nitially. in putting юgether these two pieces of int·orrnation. you might Ье 1empted to concl ude that because 1J\e highest fre­ quency of the Tay-Sachs gene appeared in the same geographic region 1hat produced the most cases of ТВ , the gene in fact of­ fers no pro1ection whaisoever. l ndeed. this was preciscly the mi staken conclнsion of many researchers who had looked at these data before. But you havc 10 рау careful a1tention to the numbers here: even at its highcst frequency the Tay-Sachs gene was carried Ьу far fewer people than would Ье infected Ьу ТВ. What the statistics really indicate is that where ТВ is the biggesl threat. natural selection produces the Ьigges1 response. Think of it this way: You arrive at an island where you find lhat all the inhaЬitants of the north end wear suits of armor, while all the inhabitants of the south end wear only cloth shirts. You'd Ье prelty safe in assuming that warfare is more prevalcnt in the norrh-and that war-related injuries account for far more deaths there than in the south. Тhus, if lhe Tay-Sachs gene does indeed lend heterozygotes some protection against ТВ, you would expect to find the gene most often precisely where you find ТВ most often. Similarly, the sickJe-cell gene reaches its highest frequencies in those parts of Africa where malaria is the Ьiggest risk. But you may Ьelieve there's still а hole in the argument: lf Tay-Sachs heterozygotes are protected against ТВ, you may Ье asking, why is the gene common just in lhe Ashkenazim? Why did it not Ьесоше comшon in the non-Jewish populations also exposed to ТВ in Austria, Hungary. and Czechoslovakia? At lhis point we must recall the peculiar circumstances in which lhe Jews of Eastern Europe were forced to live. They were unique among the world's ethnic groups in having Ьееn virtually confined to towns for most of the past 2,()(XJ years. Be­ ing forЬidden 10 own land, Eastem European Jews were not peasant farmers \iving in the countryside, but businesspeople forced ю live in crowded ghettos, in an environment where tu­ berculosis thrived. Of course, until recent improvements in sanitation, these towns were not very healthy places for non-Jews either. /ndeed, lheir populations couldn ' t sustain themselves : deaths exceeded Ьirths, and the number of dead had to Ье balanced Ьу continued emigration from the countryside. For non-Jews, lherefore, there was по genetically distinct urban population. For ghetto-bound Jew s, however, there could Ье по emigration from the countr)'­ side ; 1hus the Jewish population was under the strongest selec­ tion to evolve genetic resistaлce to ТВ. Those are the conditions that рrоЬаЫу led 10 Jcwish ТВ re­ sistance, whare ver particular genetic factors prove to unde.rlie i t. l' d speculate that Gм 2 and relatcd fats accu111ulate at slightly higher-than-norrnal levels i n heterozygotes, although nol at 1he lethal level s seen i n homozygotes. (The fat accuш ulation in het­ erozygotes рrоЬаЫу takes place in the cell шernbra11e. the cell "s "armor.") l'd also speculale that 1he accunшlation provides het­ crozygoces with sorne protection ag ainst ТВ. and 1hat that's why rhe gencs for Tay-Sachs, Gauchcr's, and Niemann-Pick disease reached high f°rcq ucnc ies in thc Ashkenazi m . Curse and Blessing of the Ghetto Having thus s1a1ed lhe case. let me make clear thal I don't want to overstate it. The evidence is still speculative. Depend­ ing on how you do the calculation, the low frequency of ТВ deaths in Tay-Sachs grandparenls either barely reachcs or doesn't quite reach the level ofproof that statistkians rcquire to accept an effect as reaJ ralher than as one tha1's arisen Ьу chance. Moreover, we have по idea of the Ьiochemical rnecha­ nism Ьу which fat accumulation might confer resistance against ТВ. For the rnornent, !' d say 1hat the evidence points 10 some se­ lective advantage of Tay-Sachs heterozygotes arnong the Ash­ kenazim, and that ТВ resistance is the onlyplausiЫe hypothesis yet proposed. For now Tay-Sachs remains а speculative model for the evo­ \ution of ethnic mseases. But it' s a\ready а proven model of what to do about them. Twenty years ago а test was developed to idenlify Tay-Sachs heterozygotes, based on 1heir lower-than­ normaJ levels of hexosarninidase А. The lest is simple, cheap, and accurate: а\11 did was to donate а small sample of my Ыооd, рау $35, and wait а few days to receive the results. lf that test shows that at least one memЬer of а couple is not а Tay-Sachs heterozygote, then any child of theirs can't Ье а Tay-Sachs homozygote. If Ьoth parents prove to Ье heterozy­ gotes, there's а one-in-four chance of their child being а ho­ mozygote; that can then Ье determined Ьу other tests performed on the mother early in pregnancy. If the results are positive, it's early enough for her to abon, should she choose to. That criticaJ bit of knowledge has enaЫed parents who had gone through the agony of bearing а Tay-Sachs ЬаЬу and watching him die to find the courage to try again. The Tay-Sachs screening program launched in the United States in 1971 was largeted at the high-risk population: Ash- kenazic Jewish couples of childЬearing age. So successful has this approach Ьееn lhat the numЬer of Tay-Sachs baЬies Ьоm each ycar in this country has declined tenfold. Today, in fact, more Tay-Sachs cases appear here in non-Jews than in Jews, Ьe­ cause only the latter couples are routinely tested. Thus. what used to Ье the classic genetic disease of Jews is so no longer. Тhere's also а broader message to the Tay-Sachs story. We commonly refer to the United States as а melting ро1, and in many ways that metaphor is apt. But in other ways we're not а melting pot, and we won 't Ье for а long time. Each elhnic group has some characteristic genes of its own, а legacy of its distinct history. TuЬerculosis and malaria are not major causes of death in the United States. but the genes that some of us evolved to protect ourselves against them are still frequent. Those genes are frequent only in certain ethnic groups, though, and they'II Ье slow to melt through the population. With modem advances in molecular genetics. we can expect to see more, not less, ethnically targeted practice of m edicine. Genetic screening for cystic fibrosis in European whites, for ex­ arnple, is one program that bas Ьееn much discussed recently; when it comes, it will surely Ье based on lhe Tay-Sachs experi­ ence. Of course, what that may mean someday is more anxiety­ ridden parents-to-Ьe glowering at more dedicated genetics counselors. lt will also mean fewer baЬies doomed to the ago­ nies of diseases we may understand but that we'U never Ье аЫе to accept. Conlributing edicor JARED DIAMOND is а profcssor of physiology at che UCLA School of Mc:dicine.