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Roger Milkman have been mapped to the appropriate locus. Whether these are maintained by selection, rather than by drift or by recombination between alleles differing at two sites, is another question. It must be remembered that the neutral hypothesis arose to explain electrophoretic variation - while not correct at this level, it may well be at others, notably synonymous variation among codons. Abundant additional evidence, mostly circumstantial, opposes the neutral hypothesis in a great variety of organisms: disparities in patterns of geographic allele-frequency variation from locus to locus; relative independence of genetic variation on population size; and correlations between allele frequencies and certain environmental variables, notably temperature. Yet the explicit ‘disproofs’ of the neutral hypothesis are few. One conclusion remains: the neutralists, led by Kimura, have made a great contribution to evolutionary genetics by sculpting away some of the dogma from the theory of natural selection and forcing its proof at the level of proteins’ primary structure.

Motoo Kimura less important molecule or a part of one molecule and therefore the evolutionary rate in it is higher. The observation that synonymous or silent substitutions (at the third position of the codon) occur more frequently in evolution per nucleotide site than missense substitutions can be explained in a similar way. On the other hand, from the selectionist viewpoint, rapidly evolving molecules or parts of a molecule have some important unknown functions and that they are undergoing rapid adaptive modifications by accumulating definitely advantageous mutations. For me at least, such an interpretation is unnatural, and when used to explain the prevalence of synonymous substitutions in evolution, it is manifestly inadequate. I admit that the neutral theory is not perfect, and I do not want to claim that it can explain all observations. Nevertheless, the fact that the theory works in not a few cases to derive predictions that are fairly close to actual observations show that it is at least a useful scientific hypothesis. References

References

1 Kimura,

1 Milkman, R. and Koehler, R. (1976) Biochem. Genei. 14, 517-522 2 Milkman, R. (1975) in Isozymes, Vol. IV, Genetics and Evolufion (Marker?, C. L., ed.), pp. 273-285, Academic Press, New York 3 Milkman, R. (1973) Science 182, 1024-1026 4 Ambler, R. P. (1974) Biochem. J. 137, 3-14

2 3 4 5

M. (1968)Nature 2 17, 624-626 Mukai, T., Schaffer, H. E. and Cockerham, C. C. (1972) Genetics 72. 763-769 Milkman, R. (1973) Science 182, 1024-1026 Kimura, M. and Crow, J. F. (1964) Generics 49, 725-738 Ohta, T. (1974) Mature 252, 351-354

The debate is now open - readers’commentswhichmay bepublishedas letters to the editorare welcome.They should be sent to the StaffEditor, 58 MuswellHillRoad, London,NJ0 ??

LETTERS TOTHE EDITOR Orbitals, conformation and biological activity Drug conformations SIR: It is obviously true, as Horn and Kennard (TIBS, May p. N 106) point out, that no amount of knowledge of the structure and conformation of a drug molecule will tell us anything of the chemical nature of its receptor. A detailed knowledge of the conformation of the drug when bound to its receptor would, however, allow us to place constraints on the geometric disposition of those groups on the receptor which

interact with the drug. The extent to which one believes that such a knowledge of the conformation in the bound state can be obtained from studies of the free drug molecule depends on one’s conceptual model of the binding process. I would agree with Kier (TIBS, April p. N 80) and Horn and Kennard that an enzyme-substrate complex may not be a good model for a drug-receptor complex. However, this should not lead us to ignore all other protein-ligand complexes - in fact the vast majority of the detailed structural information we have on enzyme-ligand interactions necessarily relates to complexes in which no covalent changes are taking place. If one accepts that many drug receptors are proteins, then at the least an examination of enzyme-ligand complexes will give one a feeling for what can happen when a drug binds to its receptor.

Kier’s model for the drug-receptor interaction, the ‘weak interaction hypothesis’, presents a number of problems. As Richards (TIBS, June p. N 131) point out, it is difficult to account for the considerable specificity of the drug-receptor interaction on the basis of weak, long-range forces. In addition, Kier’s statement that ‘a “bound” or “complexed” state is not necessary to alter materially the receptor’ must be examined in the light of the energetics of the system. He points out that, as the drug approaches the receptor, a significant interaction energy develops before the conformation of either component is perturbed. This must necessarily be the case, since the energy required for the conformational perturbation arises from the interaction energy. Indeed, the conformation can only be perturbed if the interaction energy is greater in the ‘new’ conformation. On this basis one would clearly expect that the interaction will proceed to a ‘bound’ or ‘complexed’ state. A ‘hit-and-run’ model of the kind implied by Kier is at best energetically implausible. In a real situation it is of course possible (indeed likely) that more than one form of the complex exists, and the biological effect need not necessarily be associated with the thermodynamically most stable form of the complex. The essential fact remains that if the interaction energy in

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TIBS - July 1976 a particular complex is sufficient to lead to a conformational perturbation of the receptor, then it is potentially sufficient to lead to a conformational perturbation of the drug. There is thus no reason to suppose that the conformation of the drug in the complex associated with biological activity will be the preferred conformation of the isolated drug. CORDON

ROBERTS

National Institute for Medical Research, Mill Hill, London, U.K. Models of drug-receptor events

SIR : Molecular orbital theory has demonstrated that it is possible to predict a number of structural characteristics mirroring experimental observation. One of these is the conformation preference of molecules in crystal or in solution. The latter observations are probably more relevant to the biological situation. The relevance of conformational prefer-

Sweet truth Genetic variation

SIR : It would appear that both Yudkin and Stare (see TIBS, June 1976, p. N126) are viewing the sucrose situation very simplistically. Both scientists have omitted from their discussions the role of genetics. Genetic variation in the tolerance of or requirement for a large variety of nutrients in a variety of species has been shown [l]. I would suspect that sucrose responsiveness, that is increased blood lipids or glucose intolerance or dental caries, is also genetically controlled. For example, a small percentage of the human population carries the genetic trait for maturity-onset diabetes [2]. With a diet barely sufficient in calories and containing a modest amount of refined sugar, the expression of this genetic trait might be postponed until late middle age or later, or avoided entirely. However, if the diet is over suffcient in calories and rich in refined sugars, the expression of the genetic trait may be apparent at an earlier age, perhaps coinciding with the appearance of obesity, a reduction in physical activity and an increase in the number of cigarettes smoked. The same may also be true for the appearance of carbohydrate-induced hyperlipemia. It has been estimated that approximately 12% of the adult population has this form of lipemia [3]. The development of lipemia has been thought to be related to the development of heart disease as well as diabetes. If large quantities of sucrose (or any refined sugar) are consumed as excess calories and provokes

ence to physico-chemical events near a biological receptor is a question which can only be debated, as some of the contributors in this discussion have done (see TIBS, May 1976, p N 105 and June, p. N 131). At this time, we can only construct heuristic models of the drug, the receptor, and the dynamic interplay of this system. The model must be tested against physicochemical and biological evidence. This testing in turn leads to refinement of the model, and so we iterate toward greater understanding of these events. It is important that investigators be critical at every step of the way. Hopefully, creative investigators will offer concrete suggestions to improve models of drugreceptor events. Our model (see TIBS, April 1976, p. N 80) of the importance of conformational preference at a point of remote recognition between drug and receptor is clearly provisional in the iterative process. We think that it holds a place in this point of time the expression of the genetic trait for hyperlipemia, then it might be argued that sucrose plays a role in the genesis of heart disease and/or diabetes. However, it must also be stated that the population is not at risk if they do not have the genetic trait or if they are not over nourished with respect to both total calories and carbohydrate calories. The epidemiologic studies of populations adapting to a Westernized diet all point to this idea of an interaction between diet and genetics idetermining responsiveness to sucrose, regardless of whether one considers responsiveness in terms of an increase in blood lipids, an increase in dental caries, or an increase in the incidence of diabetes. The question, then, is not whether sucrose ‘causes’ these conditions, but how can we distinguish those individuals who are at risk when consuming high calorie-high sucrose diets. Ideally, we should identify them before the onset of disease so that the expression of their genetic traits can be modified or postponed but at this point in time, we do not have the technology. CAROLYN

D. BERDANIER

University of Nebraska Medical Centre, Omaha, Nebraska, U.S.A. References I Hurley, L., ed. (1976) Fed. Proc. (in the press) 2 Vital Statistics of the United States (1971) CA 25; 14 3 Hearing before the Selecr Committee on Nutrition and Human Needs of the U.S. Senate (1973)Part 2, p. 146, U.S. Printing Offke, Washington, D.C.

as a serious model reflecting many of the characteristics of observed drug phenomena. The view that interactions are usually of weak order is also reasonable, based on current observations. A high degree of specificity between drug and receptor is just as possible with a pharamcophore orchestrating the optimum reactivity and location of weakly acting structural features as with strongly interacting features. The critical factor contributing to high specificity need only be the euphony of a three-note chord rather than the cacophony of three cymbals. I look forward with excitement to the progress which creative scientists will bring to this field. LEMONT B. KIER

Massachusetts College of Pharmacy, Boston, Massachusetts, U.S.A.

Sugar and disease SIR: It is most illustrative to compare the

philosophical approaches in the writing of JohnYudkinandFrederickStare(seeTIBS, June 1976, p. N126). Yudkin has presented the evidence linking sucrose with a number of current health problems. Not everyone will accept that evidence, but he does not call into question the integrity of those who fail to accept it. Stare, on the other hand, has engaged in an ad hominem attack on those who do accept it. Nutritionists who are critical of sugar are lumped together with food faddists, consumerists, popular writers and ‘special interests antagonistic to sugar’ and, we are told, have no qualifications in medicine or dentistry. Who are these few suspect individuals? John Yudkin? Ian Macdonals? Aharon Cohen? As a scientist I object to the debasement of science by this introduction of a spurious issue. One does not make points with a scientific audience through such an approach. It is not surprising to see Stare refer to ‘Sugar in the Diet of Man’ [l], which he contributed to and edited for the World Review of Nutrition and Dietetics. I have never seen a more one-sided series of papers in my life. The Sugar Association, Inc. has taken out full page advertisements hawking this series and has been distributing reprints free ofcharge to U.S. dietitians [2]. The advertisements claim that this series represents ‘the latest thinking on sugar from the scientific community’. I didn’t realize the scientific community was so small. When one gets down to the facts presented by Stare for the safety and useful-