THE WILLIAM ALLANMEMORIAL AWARD LECTURE

Between Two Worlds

JAMES V. NEEL

Department of Human Genetics,The University of Michigan Medical School,

Ann Arbor.

IT WAS WITH REAL PLEASURE but no little bewilderment that I received thenotification of the Allan Award. All of us enjoy being recognized. I am noexception and express to the Society my profound gratitude for this honor.But I found it all a little confusing. The committees concerned with thisAward made it quite clear in their first two presentations that they intendedto recognize contributions by the younger geneticists, there being a sufficiencyof means whereby the more senior citizen is recognized. In view of thispast, I could read only two meanings into the fact that at the ripe age of50 I found'myself in this position. One was that the Awards Committee wasbeating a strategic retreat and using me as a bridge whereby in subsequentyears they could move on to the fellow members of this Society, somewhatmy senior, who have contributed so very much to the growth of humangenetics in our day. The second interpretation of my position this afternoonwas that the Committee judges from the enthusiasm with which I haveaddressed certain subjects lately that my mental age is somewhat less thanmy chronological. This disparity can be achieved in two ways. I really do notknow which is the more gratifying, to be told that at 50 you have achievedwhat your predecessors did before 40, or to consider the possibility of theonset of that state termed by those enjoying it the summit of the years butby most onlookers, second youth.The Allan presentation is still so new that one can take off in any direction

with no fear of departing from a tradition which does not yet exist. Thisbeing the case, and feeling there is a sufficiency of formal reviews these days,I plan to speak in a rather relaxed fashion primarily to the newcomer tohuman genetics concerning a problem of increasing proportions, namely, apolarization of choices which scarcely existed some 25 years ago, when Ientered the field. More specifically, with the fantastic expansion in so manydirections of genetic knowledge, the individual just developing an interest inthis subject finds himself at an early stage under pressure to exercise somehard decisions concerning the direction of his interests. This extends farbeyond the choice of subject material, a choice which had to be exercised inmy student days, now involving also the precise nature of one's approach tothat subject material. We who advise students are in many respects under

Presented on the occasion of receiving the William Allan Memorial Award at themeeting of the American Society of Human Genetics at Seattle, August 25-27, 1965.

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no less real pressures, not only because of the traditional student-teacherrelationship but because of the relatively large sums currently available fortraining in the biomedical sciences and the knowledge that how these areused may be a decisive factor in scientific trends in the years ahead.Now, the specialization within a discipline which necessitates early and

divergent choices-and leads to difficulties in communication-is not new.Consider, for instance, biochemistry, where the recognized subareas farexceed those in genetics. Our society and our science are obviously becomingmore complicated; we in human genetics should not be surprised to sharein the trend. But I have a feeling, difficult to document, that the intellectualdistances between the emerging fields of human genetics are somewhat greaterthan between the fields of biochemistry. These distances are determined notso much by the nature of the basic concepts concerned as by the backgroundinformation and technical details which must be mastered before one canformulate and test those concepts clearly. Among these emergent, divergentpathways in human genetics, two stand out in the number who select themand the degree of their divergence, the one leading to biochemical genetics,the other to population genetics. These pathways terminate in very differentworlds, worlds between which I personally have been suspended for some-time. And at this juncture, I am sure the significance of my title is clear toall. To C. P. Snow, who has written so tellingly of the problem of the scientistand nonscientist in communicating these days (but, surprisingly enough,apparently never under this particular title), I tender my apologies fervariations on a theme he has done so much to popularize.

There are many in human genetics who will have difficulty identifyingwith either of the worlds which I have just mentioned. In particular, it wouldseem improper to leave the cytogeneticist or the clinical geneticist in limbo.But before assigning to them separate worlds-or even the closer but some-what dangerous relationship of a satellite-let us recognize some of the maincurrents there. Surely, now that the bloom of first discovery is fading, sobercytogenetics is edging over towards biochemistry, while even the "simplest"problem in clinical genetics seems either to devolve quickly into a search forthe disturbed molecule or into an epidemiological exercise in which theconcepts of population genetics are paramount (see, for example, Neel, Shaw,and Schull, 1965).

THE WORLD OF THE BIOCHEMICAL GENETICIST

The student entering the world of human biochemical genetics finds himselfin a very orderly world of solid scientific comforts. This is not an audiencewhich needs to be reminded of the florescence in our knowledge of geneticvariants of macromolecules. The techniques for detecting and characterizingthese variants being as excellent and readily available as they are, our hypo-thetical student can be reasonably sure of a worthwhile problem susceptibleto a clear formulation and reasonable solution within the time it usuallytakes to get an advanced degree. With a modicum of formal genetics and amaximum of biochemistry, he may soon be in touch with such exciting hall-

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marks of genetic respectability as operons (Neel, 1961; Motulsky, 1962; Cep-pellini, 1963), duplications (Ingram, 1961; Smithies, Connell, and Dixon,1961), unequal crossing over (Baglioni, 1962), and duplications of duplica-tions (Smithies, Connell, and Dixon, 1962; Nance and Smithies, 1963). In-deed, as was first demonstrated for the human hemoglobins (Smith, 1962),with a little extra effort he may find himself in a position to play tag with thegenetic code, thereby acquiring the scientific interlingua of our times.My personal acquaintance with this world began some 20 years ago, by

way of thalassemia and the hemoglobins. There have been quite enoughreviews of this subject in recent years; I do not intend to contribute anotherthis afternoon but only to acknowledge the good fortune which led me tothat particular problem at that particular moment. This has been a fast-movingworld full of the excitement that comes when an entirely new area opens upin which hypotheses can be rigorously tested and advance piles on advancewith really unbelievable speed. Why then abandon such a happy huntingground, as to all intents and purposes I did six to eight years ago? Theanswer is very simple. At that time it became quite clear that the biochemistryof this situation was reaching the point where, to participate in the real fun,one had to know a lot more about molecules than I did. The papers on hemo-globin in the Cold Spring Harbor Symposium of 1964 speak eloquently tothis point. It also became very clear that for some kinds of genetic problemslooming up, the approach of waiting for critical human marriages to come toattention was going to be slow and perhaps inadequate; experimental mam-mals were needed. On the more positive side, there were some stirrings andscratchings in this other world, to which we come shortly, plus the appeal ofthe less trodden path. And so, being a little beyond the age when one canrectify relative biochemical innocence without an enormous expenditure oftime and being unwilling to abandon a large investment in clinical medicinefor the pleasure of returning to working with a more easily manipulatedanimal, I transferred full time allegiance to what had for long been a secondlove.However, the individual just entering human genetics is in a different

position. He is young, very strong, very bright, and has no extensive intel-lectual investment to protect. Some considering moving in this direction mayfeel that with the elucidation of the nature of the genetic code, the opportuni-ties for truly significant work in so-called biochemical genetics have so di-minished that no real challenge is left. I can't agree with this. As many havepointed out, what has been called biochemical genetics is rapidly bringingus very close to the problems of embryonic differentiation, on a molecularlevel. Human material-specifically, the hemoglobin system-may provequite favorable for studies in this field. We probably have more detailedknowledge of the appearance of specific, functional proteins during differ-entiation for man than any other animal, and man is the only animal inwhom a genetically controlled failure of the replacement of one protein byanother, from elaboration of the y to the /3 chain of hemoglobin during fetallife, has been demonstrated (the high-F trait of Jacob and Raper, 1958; Went

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and Macdver, 1958). Further on this point, if we accept the very substantialgenetic and biochemical evidence that the gene responsible for the 8 chain ofhemoglobin A2 arose through duplication of the gene responsible for the Pchain of hemoglobin A (or vice versa) (Ingram, 1961; Baglioni, 1962), thenthe unequal production of these two types of chains during adult life presentsno less an accessible problem in the control of biochemical differentiationthan the switch from y to 8 chain production (Ingram, 1963). An indicationthat the systems regulating the minor hemoglobin components of adults maybe responsive to experimental manipulation is to be found in the increasedamounts of fetal hemoglobin sometimes encountered in individuals withchronic anemia or leukemia (Singer, Chernoff, and Singer, 1951; Beaven,Ellis, and White, 1960), although this finding may be interpreted not asdedifferentiation on a biochemical level but the activation of incompletelydifferentiated cells. The fact that in these situations (and also in thalassemiaand sickle cell disease), in contrast to the findings with the high-F trait, thefetal hemoglobin is not equally distributed among the erythrocytes (Bradley,Brawner, and Conley, 1961; Thompson, Mitchener, and Huisman, 1961;Shepard, Weatherall, and Conley, 1962) permits either of the two interpreta-tions just mentioned. One eventual experimental approach is suggested bythe report of Rucknagel and Chernoff (1955) of an increase in the concentra-tion of fetal hemoglobin in some women during pregnancy. Their suggestionthat the hormonal changes of pregnancy might be responsible antedates muchof the current interest in the hormonal regulation of gene function.

Efforts to manipulate these regulatory mechanisms need not be restrictedto the minor components. Some years ago my colleagues and I reported aneight month old infant with the sickle cell trait and severe iron deficiencyanemia in whom hemoglobin S could not be demonstrated by paper electro-phoresis until the anemia had been corrected with iron therapy (Zuelzer,Neel, and Robinson, 1956). More recently, Heller et al. (1963) reported apatient with sickle cell trait and coexistent megaloblastic anemia in whomhemoglobin S increased in concentration from an initial value of 10.6% to38.5% following therapy with folic acid, and Leere, Lichtman, and Levine(1964) described a patient with severe iron-deficiency anemia in whom theconcentration of S changed from 30 to 42% during therapy, with differentialincorporation of labeled iron into hemoglobins S and A during this period.There is thus good reason to suspect these systems may respond to the experi-mental approach.The systems whose regulation we most need to understand are perhaps

those for whose existence the evidence is only indirect. Now that the averagesize of a genetically controlled polypeptide is known and now that the natureof the genetic code is understood, it is possible to arrive at a rough estimateof the potential number of codons comprising the DNA of higher organisms.Among others, Strauss (1964) has pointed out that the DNA of man hasthe potential for coding for some 11,000,000 polypeptides, while Vogel (1964)arrived at a figure of 7,000,000. Kimura (1960), by an entirely differentapproach, had previously estimated that in the evolution of man some

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100,000,000 bits of information have been accumulated since the Cambrian era.If, as he seems to imply, a bit is the information necessary to code one aminoacid, then this is the information for coding approximately 1,000,000 poly-peptides-in addition to what was already present in Cambrian times. Thereis thus reasonable agreement between the mathematical and biological ap-proaches to this estimate. However, it seems doubtful that the number ofdifferent polypeptides in the adult human can exceed 100,000. The ratio ofestimated peptides to peptide potential is thus, roughly, between 1/50 and1/100.The observations on hemoglobin help establish a more "reasonable" ratio.

The discovery of an embryonal hemoglobin (reviewed in Huehns et al., 1964)suggests that some of this "excess" DNA may be involved in transient bio-chemical aspects of ontogeny. It will be fascinating to learn the detailedstructure of this hemoglobin. But in spite of these developments, the gapbetween the potential for coding of human DNA and the number of geneswhose activity may be inferred from macromolecules would appear to remainlarge. Kimura (1960) favors as a principal explanation of this discrepancyredundancy in the code, whereas Vogel (1964) emphasizes the possibilitythat a large fraction of the DNA is devoted to complex regulatory mechanisms.Both of these viewpoints involve a large extrapolation from the known to theunknown. Thus, although for a relatively simple organism such as Aspergillusit has been postulated that there may be two regulator genes for each struc-tural gene (Pontecorvo, 1963) and although the ratio is almost certainlygreater in higher organisms (discussion in Waddington, 1962; Bonner, 1965),thus far there are no reasons for postulating that the ratio approaches themagnitude suggested by the coding potential of human DNA. Furthermore,although there is doubtless a measure of repetition in the code (see below),we have as yet no evidence for the amount of repetition this ratio wouldsuggest.The voluminous evidence in such experimental forms as Drosophila that the

phenomenon of "pseudoallelism" is related to small, adjacent duplications(reviewed in Lewis, 1951, 1963; Carlson, 1959; Green, 1963) has long sinceled to the recognition that duplications may be an important source of "new"genes (cf. Lewis, 1951; Stephens, 1951). Evidence for the occurrence ofduplications in the mammalian genome is growing by leaps and bounds. Re-cently, I pointed out how the existence of the minor hemoglobin A2, appar-ently the result of a duplication (Ingram, 1961), directs attention to thepotentialities for suppressed genetic information in the human genome withthe possibility of continuing mutation in this information and the emergence,should repression be lost, of "new" proteins (Neel, 1964). I must now recog-nize that I was preceded in this suggestion by Zuckerkandl and Pauling(1962). It is a logical extension of this thought to see in duplications a sourceof "excess" or "outmoded" DNA. A very significant portion of the DNA forwhose functioning we now have no evidence may consist of material original-ly arising through duplication and formerly discharging a vital function (henceits fixation in the genome) but now no longer coding useful information. Thus,

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as a corollary to the concept of "evolution by duplication," we should perhapsadd "and subsequent selective loss of function." This viewpoint does not (yet)challenge the possibility that equal or even greater amounts of the "silent"DNA are devoted to either regulatory or redundant genetic information butadds another dimension to our thinking about the nature of this material. Aspreviously, the hemoglobins may again point the way to an important concept.Whichever view or views is correct, it will obviously be the work of manyyears to understand the situation.The chief counterarguments to this view of the role of a substantial fraction

of the excess DNA would appear to be that "outmoded" genetic informationshould undergo the same atrophy in the course of evolution as functionallyobsolete organs and that, if due to duplication, it should interfere with thespecificity of pairing and crossing over, as in the case of the Bar duplication.Until we know more about the mechanisms for the loss of excess DNA, it issafe to postulate that there is less genetic risk in carrying this excess baggagethan in discarding it. The almost genetically inert Y chromosomes of Droso-phila and man and the B chromosomes of maize are well known examples ofthe occurrence of large blocks of chromatin with very limited functions. Themysterious heterochromatin may merely be regions of DNA in which mostof the DNA has lost its function. The concentration of heterochromatinnear the centromere would indicate that it is especially difficult to elimi-nate outmoded DNA in this region so critical to chromosomal integrity.The pairing problem also arises with pseudoalleles and has been met byLewis (1945) with the twin suggestions that evolutionary divergence with-in the loci interferes with pairing and that these loci may involve reverserepeats. Since the duplication responsible for the 8 chain of hemoglobinappears to be present in the two African apes, Gorilla and Pan (Buettner-Janusch and Buettner-Janusch, 1964), hence presumably dating back atleast to the divergence of the hominid and other primate stocks some2,000,000 years ago, yet, as shown by hemoglobin Lepore, pairing betweenthe responsible structural genes is still possible, this locus affords someevidence concerning the time scale on which the specificity which permitspairing is lost. Studies on the A2 fraction of great apes should be of greatinterest, both to establish with certainty the homology of the ape "8"chain with the human and to compare the differences in the evolutionarycourse of these two minor hemoglobins. One might expect that the unim-portant role of A2 in oxygen transport would free it of some of the selectivepressures on hemoglobin A, with the result that the 8 chain would exhibitmore genetic variability than the /8 chain. On the other hand, one might alsoexpect fewer of these variations to have undergone genetic fixation. Con-versely, if the 8 chain has changed at the same rate as the /3, the implicationis for greater evolutionary pressures than now seem probable.

If this concept of repressed material is correct, there may be a transitorystage following complete suppression of activity in which failure of the sup-pression mechanism results in the appearance of a protein which, as a resultof continuing mutation, differs in many ways from its predecessor homologue.

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Such proteins, however, may be minor proteins, difficult to detect. At a laterstage, the accumulation of mutations may have resulted in a codon which haslost the ability to direct the synthesis of a protein. Occasionally mutants areencountered, such as polymorph in Drosophila (Neel, 1942), where thephenotypic effects are so diverse that it strains the imagination to visualizeone basic enzymatic defect. I now wonder to what extent these findings resultfrom loss of a repressor-regulator, with opportunities for the expression ofhidden genetic information well dispersed through the genome. The test ofthe hypothesis here would consist in the demonstration of multiple enzymaticdifferences from normal which cannot be explained by any single polypeptidedifference.

Returning for the moment to our student of genetics tending in this direc-tion, there is one point on which he should be very clear. Relatively speaking,it will require far more training in biochemistry than in genetics to meet thecompetition. Otherwise stated, the biochemist who along the way has hada single good course in modern genetics is probably in a better position tomake an important contribution in this field than the geneticist who has hada single or even several courses in biochemistry. In short, this is now achemist's game-it will be difficult to beat them without joining them.

THE WORLD OF THE POPULATION GENETICIST

Let's now take a look at this other world the student may be entering.It's much less tidy. Attempts to explain the origin and persistence of geneticdifferences between and within populations scored some spectacular successesin the '20's and '30's, largely from the impetus of the probing attention of justthree men, Wright, Fisher, and Haldane. But then, as attention turned tothe study of actual populations, much of that impetus was lost, despite themanner in which concern over our increasing exposure to radiation and othermutagenic agents has underscored our relative ignorance regarding popula-tion genetics. The reasons for this loss of impetus were complex, but, as faras man is concerned, two stand out. The first was the growing realization thathuman populations have until recently been very small, so small that withrespect to any given genetic system in any given small population, orderlydirective processes may break down and stochastic elements dominate de-velopments, with the introduction of a rather intractable set of mathematicalproblems. The second was that, with the many variables involved in mostformulations in population genetics, it would be extremely difficult to obtainthe kind of decisive insights which are the goal of the scientist. At the sametime, the successes of the biochemical geneticist may have diverted attentionwhich would otherwise have been directed at problems of population ge-netics, although one side issue of these successes has been the provision ofgenetic markers of enormous potential usefulness to population genetics-andthis is undoubtedly the most important advance in population genetics in thepast 20 years.

Three developments are now returning to this world some of the excitementof thirty years ago. The first is the just-mentioned proliferation of new genetic

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markers, already shown to differ widely in their frequencies from populationto population. Since each new "good" system introduces an additional, objec-tive dimension to our ability to characterize populations, we are faced witha set of coordinates in which any population has a high probability of oc-cupying a unique position.The second is the increasing availability to human biologists of the high-

speed, high-capacity computers. With these one can undertake types ofanalysis which in the past have entailed an almost prohibitive amount oflabor. Examples of the impact of these developments in human geneticswould be their application by Morton to problems of segregation analysis(reviewed in Morton, 1962), by Renwick and Schulze (1961) and Mortonto data on linkage, by Schull to multivariate and principal component analysisin studies of radiation and consanguinity effects where concomitant variablesare troublesome (Neel and Schull, 1956; Schull and Neel, 1965), by Cavalli-Sforza and Edwards to problems of human taxonomy (reviewed in Cavalli-Sforza, Barrai, and Edwards, 1964), by Newcombe and colleagues (New-combe, 1962; Newcombe and Rhynas, 1962) to the automatic linkage of avariety of official and semiofficial records into genetically meaningful aggre-gates, and by a number of people to model building (Brues, 1963; Kund-stadter et al., 1963; Schull and Levin, 1964; Barrai and Barbieri, 1964; Wil-liams, 1965).

Thirdly, now, there is the increasing ease of air transportation and travel,more important to some kinds of population genetics than others. This notonly gives the investigator ready access to populations of great interest previ-ously reached only through exhausting journeys but, even more important,ensures that within a matter of days the all-important biological specimenscan be in the hands of individuals able to subject them to the full gamutof tests. This same speedy transportation makes it possible for the investigatorto achieve his objectives in time intervals apt to prove convenient for hisuniversity.

There is a further development of a very different kind, namely, the cur-rent availability of funds for large scale field work. Our students tend to takethis for granted, never having known any other state of affairs. Sure thatmy remarks will not leave this room, I will allow as how they might all be thebetter scientists if they had to make do on an absolute shoe-string forseveral years. But lest granting agencies take too much encouragement fromthis comment, it must be emphasized that good population genetics is ex-pensive.

In the time available, it is obviously impossible to touch on all the recentdevelopments in human population genetics, any more than in human bio-chemical genetics. Under the circumstances, I will perhaps be pardonedfor discussing the work currently closest to my heart. From an early interestin the population genetics of such relatively simple traits as retinoblastoma,multiple polyposis of the colon, aniridia, Huntington's chorea, and multipleneurofibromatosis, and from a further apprenticeship on the genetic effectsof the atomic bombs, I have in recent years been caught up in two kinds

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of activities which well illustrate the impact of some of these developments.One, in which Dr. Schull is the senior partner, is concerned with consanguin-ity effects in Japan (cf. Schull and Neel, 1965). Here is an excellent example-and I can so characterize it because it is mainly Dr. Schull's work-of howthe computers can be utilized to obtain unbiased estimates, in the form ofmultivariate means, canonical correlates, or principal components, of the im-pact on interrelated indicators of a factor whose influence is confounded byall manner of socioeconomic variables. The other activity, on which I wouldlike to dwell a little longer, represents an attempt, still in its early stages, tocome to grips with some of the tantalizing problems in population geneticsoffered by the American Indian. Again, rather than subject you to anotherreview, I would like to try to look ahead a bit. Recently Salzano and I (Neeland Salzano, 1964) have subdivided these problems into three classes. Suchother groups as the Australian aborigines, the Negritoes, and the tribal groupsof India present the same types of problems.The first class of problems which now seems ready for a much more defini-

tive approach than at any time in the past is the purely taxonomic. In ouipresent n-dimensional universe of gene frequencies, now manageable becauseof the computers, what are the most probable relationships of the variousIndian tribes to one another and what, in turn, is the relationship of the Indianto other major subdivisions of the Mongolian race, such as the Polynesian.We are on the verge of major advances in human taxonomy. When Boydpublished Genetics and the Races of Man 15 years ago, he could say ofgenetic taxonomy only that it had confirmed the validity of the major sub-divisions already recognized by the physical anthropologist, with promise forthe future. At that writing, he could draw on fragmentary results from fivewell defined genetic systems (ABO, MN, Rh, PTC taster, Secretor), withvery preliminary results for several more. Now new alleles have been added tomost of these old systems, and, in addition, there are at least seven veryuseful blood group systems either not then known or just coming into view(Lutheran, Kell, Lewis, Duffy, Kidd, Diego, Sutter), plus the serum proteinsystems. In the case of such a group as the American Indian, and possibly theAustralian aborigine, hand in hand with the taxonomy is the opportunity tostudy the tempo of human evolution. What was the "rate" of genetic diver--gence following their penetration into the territory they now occupy? Andhow well will the genetic data correlate with those from archeology andlinguistics, also undergoing computerization? The recent contributions ofHanna (1962), Edwards and Cavalli-Sforza (1964), and Cavalli-Sforza, Barrai,and Edwards (1964) to the analysis of both micro- and macroevolution areexcellent examples of these taxonomic developments.The second class of problems now beckoning calls for multidisciplinary

studies of those relatively few Indian groups whose way of life is still es-sentially pre-Columbian, albeit undoubtedly to some extent altered by recentdevelopments. Since these groups so often owe their persistence to the factthat they occupy inaccessible or difficult and undesirable terrain, modernair transportation is an essential part of investigations. What exactly can we

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hope to learn from such groups? Perhaps half of this audience, perhaps more,have at one time or another spoken vaguely of recent far-reaching changes inthe genetic structure and selective pressures of human populations. The factis that we have no baseline for those statements. The existing hunting andgathering groups presumably represent man's population structure untilvery recent time. Yet, for no such group do we have extensive and accuratedata on age-specific birth and death rates, causes of death, variation in com-pleted fertility, size of breeding population, coefficient of inbreeding or fluctu-ations in population numbers. These are the parameters which influence thetempo of human evolution and which define, for instance, the relative roles ofselection and drift. Beyond this, isn't it high time to determine how trauma,nutrition, and transmissible agents interact in the disease patterns of suchgroups? Our own studies stem from the conviction that if we are ever toobtain precision in testing hypotheses concerning the origin and evolution ofhuman populations, we must have far more detailed knowledge than nowexists of genetic structure at the simplest levels of human organization.

Let me be more specific. A number of models of population structure havebeen advanced in attempts to render genetic differences between populationsamenable to quantitative treatment. While I will not argue the applicabilityof these models for contemporary civilized populations, it is clear that withrespect to the Amerindian the fission-fusion pattern of aggregation which weare encountering would appear to present features not adequately covered byany of the models now in use. The tendency for fragments of a village tobreak off periodically-these fragments being composed to a considerabledegree of related persons and having the potential either for a new tribalunit, an independent village, or joining another village-would seem on theone hand to maximize the sampling error in the formation of a tribal unit buton the other hand to render the whole tribe the breeding unit, no matter howisolated a particular village appears at a particular point in time. It also seemsvery probable that the pattern of exchange with neighboring tribes is not asimple function of distance. This point has been emphasized by Gajdusek(1964) for the tribal units of Oceania, although these may be the extremeexample of the general case.

In quite another sphere, our studies with Drs. Shope, Eveland, Brown,Stollerman, and Sodeman of gamma globulin levels and specific antibodiesreveal these groups to be under very heavy disease pressures. In recent years,our thinking about genetic resistance to disease in man has in my opinion beenunduly influenced by the sickle cell-malaria relationship. This and otherpossible similar relationships, involving such entities as thalassemia andG6PD deficiency, may in fact not involve any immunological principal at all,in the usual sense of the word, but a shortened erythrocyte survival time understress which creates conditions unfavorable to the malaria life cycle (Miller,Neel, and Livingstone, 1956; Neel, 1962a). Recently Brewer and Powell (1965)have evidence that, following experimental infections with Plasmodium falci-parum, parasitemia builds up more slowly in Negro males whose ATP levelsare relatively low. This observation can be very nicely fitted into the afore-

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mentioned pattern. Thus, the malaria parasite as a relative newcomer on thescene may by virtue of its unusual life cycle have elicited a type of "tempo-rary or transitory genetic response not at all typical of the genetic responseusually responsible for relative disease resistance, as illustrated, for example,by mouse typhoid (reviewed in Gowen, 1963). In this connection, we aremost interested to see what the distribution of positive antibody responseswill be-Poissonian or, as seems more likely, some type of negative binomial,and, if the latter, are there familial patterns?As the last example of the kinds of problems we would like to approach,

I should mention efforts to measure intelligence and relate it to reproductivepatterns. The outstanding development in human evolution in the past millionyears has of course been the increase in the size and complexity of the brain.This implies that intelligence carried an increased probability of survival andreproduction. At first glance, from our materialistic vantage point, there seemslittle chance to exercise superior intelligence in these "simple" cultures. Butfor survival and the prestige that brings additional wives, the individual in theso-called simple culture must in fact often master at least as complex a setof ground rules as we highly civilized folk. Consider, for example, the elabo-rate kinship and theistic systems of perhaps the least evolved of all humanstrains, the Australian aborigine (cf. Elkin, 1954). Although the period ofrelatively rapid evolution of cerebral function may well be past, perhaps inthese surviving simple cultures there are still a few clues as to the natureof the selective forces involved.

Hopefully, from a variety of studies along these and other lines, we may intime deduce the knowledge necessary to convert the Index of Potential Selec-tion developed by Crow (1958) into an Index of Actual Selection, to becompared with similar indices for highly civilized groups. Here is perhaps theplace to record that, while I see no lack of specific questions to be asked, Ihope soon to arrange an expedition so scheduled that there is time simplyto sit and observe for a while. It is very much on my mind that we do notyet know these groups well enough to formulate the proper questions.

Thirdly, we come to a class of problems stemming from the opportunitieswhich the Amerindian offers to study the impact of a rapidly changing en-vironment on disease patterns, a line of investigation of practical value to theIndian as well. Although the cultural milieu is changing rapidly for all man-kind, it is changing especially rapidly for the Amerindian and similar groups.Will genetic predispositions emerge unusually strongly under these conditions?For instance, some time ago I suggested that the genotype susceptible todiabetes mellitus might in times past have been at a metabolic advantagebecause of its ability to mobilize insulin quickly (Neel, 1962b). Studies ofglucose metabolism, and especially the level of serum insulin and insulinantagonists, in primitive and recently primitive populations offer a partial testof this hypothesis. Similar possibilities exist with respect to the regulation ofblood pressure or serum cholesterol.

I offer the above simply as an example of what is brewing in one aspect ofpopulation genetics. The prospects in other branches of human population

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genetics are certainly no less exciting. There are difficulties, to be sure. Forinstance, in the studies of the simple cultures, we are working under severetime restrictions; these groups are rapidly disappearing. Whether our method-ology will develop sufficiently rapidly to extract maximum information fromsuch groups as are still intact prior to their disintegration cannot be predicted.If it could, much of the uncertainty that lures us into research would bemissing. But despite my concern for the problems ahead, I obviously don'tconsider the prospects in quite the same light as a distinguished critic of mygenetic life and times, who has recently termed the type of study which weare currently conducting on the Xavante Indians "the intensive investigationof a historical accident interposed between arbitrary definition and extinc-tion" and who further stated that "despite the demographic interest of suchunrepeatable experiments, which maximize the ratio of noise to signal, theircontribution to population genetics is limited" (Morton, 1964). From thisexercise in pejoration, it is not at all clear to me under what circumstancesMorton believes human evolution to have occurred. Otherwise stated, whatkinds of populations would he consider apposite to efforts to understand thesignificant parameters in human evolution?

In biochemical genetics, such is the present control over the material thatclear and unequivocal acceptance or rejection of hypothesis should be therule. While we will from time to time have that pleasure in human popula-tion genetics, it will often, perhaps usually for some time to come and formany classes of problems, be otherwise. For example, given genetic differencesbetween two groups, we will seldom be able to say with assurance, "this isdue to selection," "this is due to drift," or "one of these populations hasbeen more subject to exchange with its neighbors than the other." Thesame problem may arise in understanding specific systems within popula-tions. Apparent concurrence with one hypothesis will in this field seldomexclude others, as is so well illustrated by the very diverse hypotheses bywhich we are capable of explaining the persistence of the ABO and MNpolymorphisms (Morton and Chung, 1959; Chung and Morton. 1961; Mat-sunaga and Hiraizumi, 1962; Hiraizumi, 1964a, b). I am in this connectionreminded of a passage in Balthazar wherein Durrell credits Pursewardenwith the following remark: "We live lives based upon selected fictions. Ourview of reality is conditioned by our position in space and time-not byour personalities as we like to think. Thus every interpretation of reality isbased upon a unique position. Two paces east or west and the whole pictureis changed."An approach whose utility is still largely unexplored in these situations,

made possible by the high capacity computers, is repeated machine simula-tion, as described by Schull and Levin (1964) but now based on models ofthe actual populations concerned-and this is why we must know our popu-lations. This leads to a range of answers of varying probability, a topographyof solutions as it were. More specifically, let us assume that we are concernedto explain the origin of the genetic differences between two tribes of Indianswhose population structure and dynamics we have studied to the best of

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our ability. Assuming a common origin with gene frequencies as suggestedby our taxonomy, we now ask what are the expected distributions of genefrequencies at a specific locus for the two populations under the best as-sumptions we can make and how do the observed differences compare withthe expected. By the time we have done this for a dozen loci we have arather powerful approach. If the observed differences at these dozen loci areeither consistently more or less than we expect, we know our assumptions andour models need reworking. If, on the other hand, the results are as predictedby the model, we may be on the right track. In short, we need not ask suchrestricted and perhaps misleading questions as: "Are the findings consistentwith selection?" "Could drift have done it?" "Is this gene maintained bymutation?" Instead, we are free to pursue a more holistic approach. Thereby,by avoiding that premature attachment to a special point of view so charm-ingly described by Chamberlin in 1890 under the title, "The method ofmultiple working hypotheses," we will take full advantage of the potentialitiesof the computers.

This recourse to simulation does not imply we need not constantly striveto keep our approach sharp but rather suggests we must be prepared to dealin this field much more in probabilities than in absolutes. I suppose the out-standing example in recent years of an attempt at a clear cut formulationwhich should lead to a decision between two alternative hypotheses in popu-lation genetics was the ingenious attempt of Morton, Crow, and Muller (1956)to utilize data from inbreeding to get at the relative importance of mutationaland segregational loads. Elsewhere, we as well as others have reviewed themany reasons why that attempt, stimulating though it has been, has fallenfar short of its goals (Schull and Neel, 1965), as may other similar attempts.In my opinion our objectives for the next several decades must be on thehumble side; we will make great relative progress, with much more to buoyus up than, as Beam, Bowman, and Kitchin (1964) so well put it, the Bacon-ian concept that all knowledge is useful, but we may seldom deal in absolutesolutions. Some 11 years ago, in a presidential address to this Society, I empha-sized the dangers of erecting hypotheses incorporating variables, such aspenetrance, that prevent clear test of the hypothesis. This is not a retreatfrom that position but a recognition that, in situations where we cannot con-trol the variables, we have new tools with which to assign them a properrole (Neel, 1955).

Earlier I emphasized the degree of training in biochemistry necessary tothe biochemical "geneticist" hoping for significant participation in his field.Now I must emphasize that the "new" population geneticist will routinelyneed a degree of training in the mathematical aspects of genetics, including,now, computer talk, which in my days as a graduate student was acquiredby a select few.

Further, it will be increasingly difficult to delineate worthwhile problemsin this field which can be adequately treated with the time and resourcesavailable to most graduate students. The student will often find himselfworking as one of a "team," wherein many members contribute special skills

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to the elaboration and analysis of the data. This requires a blending of indi-vidual interests which is foreign to the individualistic nature of many highlycreative persons. And lest I be accused of going overboard for team research,let me recognize clearly that too much of team research seems dominated bythe concept that if one confused man can't solve a problem, perhaps sixequally confused men working together can. There is, to be sure, a finiteprobability that they can combine their respective limping insights into amoment of truth. There is also a finite probability that they can combinetheir respective confusions into a catastrophic mess.

CLOSING REMARKS

A presentation such as this does not lend itself to the nice, crisp "Summaryand Conclusions" type of ending. I have attempted to view with you a trendof our genetic times, especially as it affects the student, colored by thepersonal experiences which have resulted in my being in the position inwhich I now find myself. The contrast between the concepts and methodologyof the two fascinating worlds, which I have discussed in so brief and frag-mentary a fashion, and between other lines of genetic inquiry can only in-crease in the future. Doing first-rank work these days requires a depth ofpreparation which, for ordinary minds at least, is increasingly incompatiblewith true breadth. You were undoubtedly as aware of this trend as I havebeen. And we in genetics are of course not unique in trying to cope withspecialization and the problems in communication it creates, only sharinga basic dilemma of our culture which has been the subject of repeated essays.And yet, with the growing consequences of scientific discoveries and withthe growing participation of scientists in the problems of their nation, neverwas the need for breadth, extending well beyond the confines of science,greater. In view of the seeming special relevance of genetic knowledge tohuman affairs, what can or should we in genetics be doing to meet thesetrends?We will certainly agree that the techniques for intellectual exchange be-

tween components of our culture and for incorporating scientific knowledgeinto social affairs and vice versa are woefully inadequate. Isn't it time weteachers instilled into students the same respect for good synthesizers and goodadministrators in science as we do for good investigators. Surely the scientist,who has made major contributions to the grave situation in which mankindfinds itself, is not immune from the responsibilities of other respected citizens.In fact, in return for the privileged position we have come to occupy, we reallyhave special responsibilities, a position most dramatically illustrated by thephysicist (cf. Oppenheimer, 1964). We cannot indefinitely escape to theendless frontier (cf. Price, 1965). If we accept the proposition that our sci-ence and our society will be stronger if we stay within intellectual hailingdistance of one another, then, unless communications are improved, the onlyapparent solution to the problem of lessening these growing distances, withingenetics, within science, or for science vis-a-vis the humanities, is a decelera-tion of the tempo of research. But even should this alternative, which is not

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apt to be enthusiastically endorsed by scientists, be considered advisable, howto effect it in a world of intense scientific and technological competition?Perhaps, as Platt (1965) has suggested, we are approaching a "steady state"situation where the deceleration will not involve a conscious adjustment onour part.At the very least, on our own small scale, I may be permitted to view with

alarm the growing tendency for special interest groups to withdraw fromthe general meetings when matters not of direct interest to them are beingdiscussed. For the newcomer, the intellectual togetherness which I am urgingmay imply an additional year of preparation, but with the present level offellowship support there is so little difference between a fellowship and afaculty appointment that I doubt this would be objectionable. On the otherhand, as genetics becomes ever more precise, the "age of maximum achieve-ment" should move downward, as in mathematics and physics; there is dangerthat the medically trained individual who adds genetic and some technicaltraining to his repertoire misses an important fraction of his potentially mostproductive years.

In summary, I can only suggest what is perhaps obvious to all of you, thatnow that human genetics is something the potential student can be exposed torelatively early, it is to be hoped that more and more minds will be captured inthe first flush of creativity, after which we as teachers can strive to assistthese minds in acquiring a broad base not limited to science, an awarenessof the tempo of the times, and technical competence in one area. Some of thenewcomers may find the precise choice of direction difficult. I assure you thetimes are no less trying but exciting for some of your seniors, who have foundthemselves with an attachment in several of the worlds of genetics as theymoved apart.

Finally, now, in closing let me recognize the extent to which the activitieswhich lead me to speak to you this afternoon have profited from the generousand warm-hearted co-operation of a long series of colleagues and associates,to whom I am grateful in a way that I simply cannot verbalize.

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