[In] the evolution of ideas… New ideas are thrown up spontaneously like mutations; the vast majority of them are useless crank theories, the equivalent of biological freaks without survival-value.

A comparison between the triplets tentatively deduced by these methods with the changes in amino acid sequence produced by mutation shows a fair measure of agreement.

A final proof of our ideas can only be obtained by detailed studies on the alterations produced in the amino acid sequence of a protein by mutations of the type discussed here.

Attempts have been made from a study of the changes produced by mutation to obtain the relative order of the bases within various triplets, but my own view is that these are premature until there is more extensive and more reliable data on the composition of the triplets.

By 1999, over 880 studies suggested that some mutations might … be genetic alterations “custom tailored” to overcome emergencies.

Every species of plant and animal is determined by a pool of germ plasm that has been most carefully selected over a period of hundreds of millions of years. We can understand now why it is that mutations in these carefully selected organisms almost invariably are detrimental.The situation can be suggested by a statement by Dr. J.B.S. Haldane: “My clock is not keeping perfect time. It is conceivable that it will run better if I shoot a bullet through it; but it is much more probable that it will stop altogether.” Professor George Beadle, in this connection, has asked: “What is the chance that a typographical error would improve Hamlet?”

Evolutionary plasticity can be purchased only at the ruthlessly dear price of continuously sacrificing some individuals to death from unfavourable mutations. Bemoaning this imperfection of nature has, however, no place in a scientific treatment of this subject.

Faced with a new mutation in an organism, or a fundamental change in its living conditions, the biologist is frequently in no position whatever to predict its future prospects. He has to wait and see. For instance, the hairy mammoth seems to have been an admirable animal, intelligent and well-accoutered. Now that it is extinct, we try to understand why it failed. I doubt that any biologist thinks he could have predicted that failure. Fitness and survival are by nature estimates of past performance.

I do ... humbly conceive (tho' some possibly may think there is too much notice taken of such a trivial thing as a rotten Shell, yet) that Men do generally rally too much slight and pass over without regard these Records of Antiquity which Nature have left as Monuments and Hieroglyphick Characters of preceding Transactions in the like duration or Transactions of the Body of the Earth, which are infinitely more evident and certain tokens than any thing of Antiquity that can be fetched out of Coins or Medals, or any other way yet known, since the best of those ways may be counterfeited or made by Art and Design, as may also Books, Manuscripts and Inscriptions, as all the Learned are now sufficiently satisfied, has often been actually practised; but those Characters are not to be Counterfeited by all the Craft in the World, nor can they be doubted to be, what they appear, by anyone that will impartially examine the true appearances of them: And tho' it must be granted, that it is very difficult to read them, and to raise a Chronology out of them, and to state the intervalls of the Times wherein such, or such Catastrophies and Mutations have happened; yet 'tis not impossible, but that, by the help of those joined to ' other means and assistances of Information, much may be done even in that part of Information also.

I have attempted to form a judgment as to the conditions for evolution based on the statistical consequences of Mendelian heredity. The most general conclusion is that evolution depends on a certain balance among its factors. There must be a gene mutation, but an excessive rate gives an array of freaks, not evolution; there must be selection, but too severe a process destroys the field of variability, and thus the basis for further advance; prevalence of local inbreeding within a species has extremely important evolutionary consequences, but too close inbreeding leads merely to extinction. A certain amount of crossbreeding is favorable but not too much. In this dependence on balance the species is like a living organism. At all levels of organization life depends on the maintenance of a certain balance among its factors.

In Darwin’s theory, you just have to substitute ‘mutations’ for his ‘slight accidental variations’ (just as quantum theory substitutes ‘quantum jump’ for ‘continuous transfer of energy’). In all other respects little change was necessary in Darwin’s theory.

In systemic searches for embryonic lethal mutants of Drosophila melanogaster we have identified 15 loci which when mutated alter the segmental patterns of the larva. These loci probably represent the majority of such genes in Drosophila. The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.
[Co-author with American physiologist Eric Wieshaus (1947-)]

In the beginning was the word
WORD
WORE
GORE
GONE
GENE
and by the mutations came the gene.

Investigating the conditions under which mutations occur … requires studies of mutation frequency under various methods of handling the organisms. As yet, extremely little has been done along this line. That is because, in the past, a mutation was considered a windfall, and the expression “mutation frequency” would have seemed a contradiction in terms. To attempt to study it would have seemed as absurd as to study the conditions affecting the distribution of dollar bills on the sidewalk. You were simply fortunate if you found one. … Of late, however, we may say that certain very exceptional banking houses have been found, in front of which the dollars fall more frequently—in other words, specially mutable genes have been discovered, that are beginning to yield abundant data at the hands of Nilsson-Ehle, Zeleny, Emerson, Anderson and others.

It is possible that the deepest meaning and aim of Newtonianism, or rather, of the whole scientific revolution of the seventeenth century, of which Newton is the heir and the highest expression, is just to abolish the world of the 'more or less', the world of qualities and sense perception, the world of appreciation of our daily life, and to replace it by the (Archimedean) universe of precision, of exact measures, of strict determination ... This revolution [is] one of the deepest, if not the deepest, mutations and transformations accomplished—or suffered—by the human mind since the invention of the cosmos by the Greeks, two thousand years before.

It seems to me that the view toward which we are tending is that the specificity in gene action is always a chemical specificity, probably the production of enzymes which guide metabolic processes along particular channels. A given array of genes thus determines the production of a particular kind of protoplasm with particular properties—such, for example, as that of responding to surface forces by the formation of a special sort of semipermeable membrane, and that of responding to trivial asymmetries in the play of external stimuli by polarization, with consequent orderly quantitative gradients in all physiologic processes. Different genes may now be called into play at different points in this simple pattern, either through the local formation of their specific substrates for action, or by activation of a mutational nature. In either case the pattern becomes more complex and qualitatively differentiated. Successive interactions of differentiated regions and the calling into play of additional genes may lead to any degree of complexity of pattern in the organism as a largely self-contained system. The array of genes, assembled in the course of evolution, must of course be one which determines a highly self­regulatory system of reactions. On this view the genes are highly specific chemically, and thus called into play only under very specific conditions; but their morphological effects, if any, rest on quantitative influences of immediate or remote products on growth gradients, which are resultants of all that has gone on before in the organism.

Judged superficially, a progressive saturation of the germ plasm of a species with mutant genes a majority of which are deleterious in their effects is a destructive process, a sort of deterioration of the genotype which threatens the very existence of the species and can finally lead only to its extinction. The eugenical Jeremiahs keep constantly before our eyes the nightmare of human populations accumulating recessive genes that produce pathological effects when homozygous. These prophets of doom seem to be unaware of the fact that wild species in the state of nature fare in this respect no better than man does with all the artificality of his surroundings, and yet life has not come to an end on this planet. The eschatological cries proclaiming the failure of natural selection to operate in human populations have more to do with political beliefs than with scientific findings.

Language is simply alive, like an organism. We all tell each other this, in fact, when we speak of living languages, and I think we mean something more than an abstract metaphor. We mean alive. Words are the cells of language, moving the great body, on legs. Language grows and evolves, leaving fossils behind. The individual words are like different species of animals. Mutations occur. Words fuse, and then mate. Hybrid words and wild varieties or compound words are the progeny. Some mixed words are dominated by one parent while the other is recessive. The way a word is used this year is its phenotype, but it has deeply immutable meanings, often hidden, which is its genotype.... The separate languages of the Indo-European family were at one time, perhaps five thousand years ago, maybe much longer, a single language. The separation of the speakers by migrations had effects on language comparable to the speciation observed by Darwin on various islands of the Galapagos. Languages became different species, retaining enough resemblance to an original ancestor so that the family resemblance can still be seen.

Mutation is random; natural selection is the very opposite of random

Mutations and chromosomal changes arise in every sufficiently studied organism with a certain finite frequency, and thus constantly and unremittingly supply the raw materials for evolution. But evolution involves something more than origin of mutations. Mutations and chromosomal changes are only the first stage, or level, of the evolutionary process, governed entirely by the laws of the physiology of individuals. Once produced, mutations are injected in the genetic composition of the population, where their further fate is determined by the dynamic regularities of the physiology of populations. A mutation may be lost or increased in frequency in generations immediately following its origin, and this (in the case of recessive mutations) without regard to the beneficial or deleterious effects of the mutation. The influences of selection, migration, and geographical isolation then mold the genetic structure of populations into new shapes, in conformity with the secular environment and the ecology, especially the breeding habits, of the species. This is the second level of the evolutionary process, on which the impact of the environment produces historical changes in the living population.

Mutations merely furnish random raw material for evolution, and rarely, if ever determine the course of the process.

Since many cases are known in which the specificities of antigens and enzymes appear to bear a direct relation to gene specificities, it seems reasonable to suppose that the gene’s primary and possibly sole function is in directing the final configurations of protein molecules.
Assuming that each specific protein of the organism has its unique configuration copied from that of a gene, it follows that every enzyme whose specificity depends on a protein should be subject to modification or inactivation through gene mutation. This would, of course, mean that the reaction normally catalyzed by the enzyme in question would either have its rate or products modified or be blocked entirely.
Such a view does not mean that genes directly “make” proteins. Regardless of precisely how proteins are synthesized, and from what component parts, these parts must themselves be synthesized by reactions which are enzymatically catalyzed and which in turn depend on the functioning of many genes. Thus in the synthesis of a single protein molecule, probably at least several hundred different genes contribute. But the final molecule corresponds to only one of them and this is the gene we visualize as being in primary control.

So, let’s say you want to change the human body. You want to fix a mistake. You want to repair something. You want to improve something. Well, if you’re going to reprogram human genetic material, you need a delivery system, and nothing works better than virus. It’s like a suitcase. Yes, pack in genetic mutation infect the body and the vector loads into the target cells Getting it where you want it, how you want it, is the nightmare. Unless you have a map.

The central problem of biological evolution is the nature of mutation, but hitherto the occurrence of this has been wholly refractory and impossible to influence by artificial means, although a control of it might obviously place the process of evolution in our hands.

The Epicureans, according to whom animals had no creation, doe suppose that by mutation of one into another, they were first made; for they are the substantial part of the world; like as Anaxagoras and Euripides affirme in these tearmes: nothing dieth, but in changing as they doe one for another they show sundry formes.

The function of mutation is to maintain the stock of genetic variance at a high level.

The main steps of my argument may be summarized thus:
1. Organisms are highly coordinated structures.
2. Only certain avenues of change are compatible with their conditions of coordination.
3. The formative and selective action of these internal conditions is theoretically and empirically different from that of Darwinian selection.
4. Mutations in the mode of coordination of the genetic system lie outside the scope of the classical arguments purporting to show that natural selection is the only directive agency.
5. The coordinative conditions constitute a second directive agency.

The majority of evolutive movements are degenerative. Progressive cases are exceptional. Characters appear suddenly that have no meaning in the atavistic series. Evolution in no way shows a general tendency toward progress… . The only thing that could be accomplished by slow changes would be the accumulation of neutral characteristics without value for survival. Only important and sudden mutations can furnish the material which can be utilized by selection.

The messages that DNA molecules contain are all but eternal when seen against the time scale of individual lifetimes. The lifetimes of DNA messages (give or take a few mutations) are measured in units ranging from millions of years to hundreds of millions of years; or, in other words, ranging from 10,000 individual lifetimes to a trillion individual lifetimes. Each individual organism should be seen as a temporary vehicle, in which DNA messages spend a tiny fraction of their geological lifetimes.

The moment man first picked up a stone or a branch to use as a tool, he altered irrevocably the balance between him and his environment. From this point on, the way in which the world around him changed was different. It was no longer regular or predictable. New objects appeared that were not recognizable as a mutation of something that existed before, and as each one merged it altered the environment not for one season, but for ever.

The process of mutation is the only known source of the raw materials of genetic variability, and hence of evolution. It is subject to experimental study, and considerable progress has been accomplished in this study in recent years. An apparent paradox has been disclosed. Although the living matter becomes adapted to its environment through formation of superior genetic patterns from mutational components, the process of mutation itself is not adaptive. On the contrary, the mutants which arise are, with rare exceptions, deleterious to their carriers, at least in the environments which the species normally encounters. Some of them are deleterious apparently in all environments. Therefore, the mutation process alone, not corrected and guided by natural selection, would result in degeneration and extinction rather than in improved adaptedness.

The proof given by Wright, that non-adaptive differentiation will occur in small populations owing to “drift,” or the chance fixation of some new mutation or recombination, is one of the most important results of mathematical analysis applied to the facts of neo-mendelism. It gives accident as well as adaptation a place in evolution, and at one stroke explains many facts which puzzled earlier selectionists, notably the much greater degree of divergence shown by island than mainland forms, by forms in isolated lakes than in continuous river-systems.

The secrets of evolution are death and time—the deaths of enormous numbers of lifeforms that were imperfectly adapted to the environment; and time for a long succession of small mutations.

The theory here developed is that mega-evolution normally occurs among small populations that become preadaptive and evolve continuously (without saltation, but at exceptionally rapid rates) to radically different ecological positions. The typical pattern involved is probably this: A large population is fragmented into numerous small isolated lines of descent. Within these, inadaptive differentiation and random fixation of mutations occur. Among many such inadaptive lines one or a few are preadaptive, i.e., some of their characters tend to fit them for available ecological stations quite different from those occupied by their immediate ancestors. Such groups are subjected to strong selection pressure and evolve rapidly in the further direction of adaptation to the new status. The very few lines that successfully achieve this perfected adaptation then become abundant and expand widely, at the same time becoming differentiated and specialized on lower levels within the broad new ecological zone.

The universe came into being in a big bang, before which, Einstein’s theory instructs us, there was no before. Not only particles and fields of force had to come into being at the big bang, but the laws of physics themselves, and this by a process as higgledy-piggledy as genetic mutation or the second law of thermodynamics.

The Zebra fish is a vertebrate like us, but unlike mammals, you can get at the embryo which grows fast and hatches within three days. The fish lays lots of transparent eggs, so you have a lot of material to work with. One can watch everything developing: the formation of the nervous system, eyes, brain, and body. … We can see that embryo, follow its growth, and see effects of mutations immediately.

There has been a very large number of mutations discovered in the laboratory races of Drosophila melanogaster Meigen…. It…would be of considerable interest to get an idea of how these mutations compare with the differences between wild species of Drosophila.

There is a finite number of species of plants and animals—even of insects—upon the earth. … Moreover, the universality of the genetic code, the common character of proteins in different species, the generality of cellular structure and cellular reproduction, the basic similarity of energy metabolism in all species and of photosynthesis in green plants and bacteria, and the universal evolution of living forms through mutation and natural selection all lead inescapably to a conclusion that, although diversity may be great, the laws of life, based on similarities, are finite in number and comprehensible to us in the main even now.

We do not know of any enzymes or other chemical defined organic substances having specifically acting auto-catalytic properties such as to enable them to construct replicas of themselves. Neither was there a general principle known that would result in pattern-copying; if there were, the basis of life would be easier to come by. Moreover, there was no evidence to show that the enzymes were not products of hereditary determiners or genes, rather than these genes themselves, and they might even be products removed by several or many steps from the genes, just as many other known substances in the cell must be. However, the determiners or genes themselves must conduct, or at least guide, their own replication, so as to lead to the formation of genes just like themselves, in such wise that even their own mutations become .incorporated in the replicas. And this would probably take place by some kind of copying of pattern similar to that postulated by Troland for the enzymes, but requiring some distinctive chemical structure to make it possible. By virtue of this ability of theirs to replicate, these genes–or, if you prefer, genetic material–contained in the nuclear chromosomes and in whatever other portion of the cell manifests this property, such as the chloroplastids of plants, must form the basis of all the complexities of living matter that have arisen subsequent to their own appearance on the scene, in the whole course of biological evolution. That is, this genetic material must underlie all evolution based on mutation and selective multiplication.

We find in the history of ideas mutations which do not seem to correspond to any obvious need, and at first sight appear as mere playful whimsies—such as Apollonius’ work on conic sections, or the non-Euclidean geometries, whose practical value became apparent only later.