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Robin Holliday

Publications and source records attributed to Robin Holliday.

18 recordsLinked to original sources
PubMed2006

Meiosis and sex: potent weapons in the competition between early eukaryotes and prokaryotes.

The earliest eukaryote species almost certainly evolved in an environment dominated by numerous prokaryotic species. If the first eukaryotic cells were larger and grew more slowly than their prokaryotic neighbours, they might well have been at a competitive disadvantage. It is proposed here that the early evolution of meiosis, with its capacity for generating new favourable gene combinations, might have served to offset any such competitive disadvantages. Meiosis and sex could have arisen in an asexually reproducing species and formed a clonal population.

Animals↗
PubMed2006

Physics and the origins of molecular biology.

Bohr, Delbrück and Schrödinger were physicists who had important influences on biology in the second half of the twentieth century. They thought that future studies of the gene might reveal new principles or paradoxes, analogous to the wave/particle paradox of light propagation, or even new physical laws. This stimulated several physicists to enter the field of biology. Delbrück founded the bacteriophage group which provided one of the roots of molecular biology. Another was X-ray crystallography which led to the discovery of DNA structure. The strength and success of molecular biology came from the many interactions between geneticists, physicists, chemists and biochemists. It was also characterized by a powerful combination of theoretical and experimental approaches.

Animals↗
PubMed2006

Food, fertility and longevity.

Some animals live in environments in which the food supply fluctuates. When it is scarce these animals do not breed, but invest resources into survival until food is again available, and they can reproduce. Under these circumstances the lifespan can be increased, just as it is after calorie restriction. Other animals have a fairly constant food supply, and it is predicted that these would not have an extended life span if subjected to calorie restriction. Hibernation is a natural form of calorie restriction, and in some cases may lengthen lifespan.

Adaptation, Physiological↗
PubMed2006

Aging is no longer an unsolved problem in biology.

For much of the 20th century, the accumulation of a considerable amount of information about the processes of aging did not reveal the underlying mechanisms. Toward the end of that century, the biological basis for aging became very much clearer. It became apparent that the best strategy for animals' survival was to develop to an adult, but not to invest resources in maintaining the body, or soma, indefinitely. In their natural environment, animals do not survive environmental hazards (predators, disease, starvation, and drought) to reach a long life span. There is thus a trade-off between the investment of resources in reproduction, and the survival time of the soma. At a stroke, this solves the problem of different rates of aging in different species, because those that develop and reproduce fast also have short life spans, and those that develop and reproduce slowly have long life spans. This difference is due to actual resources invested in the maintenance of the adult soma. There is now much evidence that long-lived mammals have much more efficient maintenance mechanisms than short-lived mammals. Thus, aging can be defined as the eventual failure of maintenance. It also became apparent that many different maintenance mechanisms exist, and that these depend on very many genes and a considerable investment in metabolic resources. Most individual theories of aging revolve around the failure of a given maintenance system, but as there are many of these, it is likely that most of the important theories have some degree of truth. A broad interpretation of the different degenerative changes during senescence should therefore be adopted, with the major conclusion that aging is multicausal. It is also evident that the evolved design of many components of complex animals is incompatible with indefinite survival. We can therefore conclude that this evolved design is intrinsically related to the fact of aging. This in turn means that aging cannot be reversed, although it may be modulated, as, for example, by calorie restriction.

Aging↗
PubMed2005

Ageing and the extinction of large animals.

In the modulation of longevity by natural selection there is a trade-off between the investment of resources in the maintenance of the body, or soma, and the investment in reproduction. There is accumulating evidence that long-lived mammalian species have much more efficient maintenance than short-lived ones. It is also clear that short-lived ground-living mammalian species reproduce very much more quickly than larger long-lived species, and in all mammals there is an inverse relationship between maximum reproductive potential and maximum longevity. These features of life-history strategies very strongly support the disposable soma theory of the evolution of ageing. Slow development and large size are associated with delayed ageing. If the environment changes, for whatever reason, small rapidly breeding species are able to adapt and survive much more easily that large slow breeding species. This can explain the very well documented extinction of many large mammalian species during the Pleistocene. In an environment which remains constant for a long period of time, selection favours the evolution of larger species, but these are put at risk if the environment becomes less favorable. Fluctuating environments are more likely to promote the evolution of small short-lived species with high fecundity.

Aging↗
PubMed2005

Evolution of human longevity, population pressure and the origins of warfare.

In a protected environment, humans have the longest lifespan of all primates. However, during the emergence of Homo sapiens from pre-hominids, the expectation of life at birth would have been quite low. On the basis of reasonable assumptions, an average expectation of life of less than 20 years is sufficient to maintain a population of hunter-gatherers. As individuals became better adapted to their environment, the mortality rate would gradually decrease, and this would result in the survival of more offspring to adulthood. Thus, the population will increase, and one of the consequences in human evolution is the migration of human communities to many new habitats. The development of agriculture provided a more reliable source of food, and stimulated further the increase in population size. Villages became towns, and then cities, states and empires arose which had very large populations, and competed for land and other resources. Armies were raised and were often at war. All this was due to population pressure, as Malthus had realised more than 200 years ago. However, neither he, nor any of the others who discussed warfare, understood that the demographic changes that produced large human populations was a steady increase in the expectation of life at birth. This inevitably occurred at the same time as man gradually gained more control over his environment, and achieved far more reproductive success than is seen in hunter-gatherers living in a harsh, stressful environment.

Agriculture↗
PubMed2004

Early studies on recombination and DNA repair in Ustilago maydis.

This historical review covers the period 1960 to mid-1980s. The first experiments were carried out at the John Innes Institute, Bayfordbury, Hertford, with a one year interlude in the Department of Genetics, University of Washington, Seattle. In 1965, I moved to the National Institute for Medical Research, Mill Hill, London, and became head of a new Genetics Division. The research on Ustilago was divided broadly into (1) experimental genetic studies, and (2) DNA enzymology, largely under the direction of the late Geoffrey Banks. The approaches involved isolating and characterizing mutants defective in repair and recombination (the first in any eukaryotic organism), with the longer term aim of identifying the function of genes through studies of enzymes and proteins which interact with DNA. An enzyme capable of recognizing mismatched bases in DNA was identified. A novel method exploited the inducible nitrate reductase gene, and revealed relationships between recombination, mutation, repair, transcription and cell survival. Several different studies provide strong evidence for the presence of an inducible repair pathway, dependent on recombination. Much more recently, the revolution in molecular genetics has been in exploited in several laboratories working with Ustilago maydis, and these have produced some completely new insights into recombination and repair.

Cell Survival↗
PubMed2004

The close relationship between biological aging and age-associated pathologies in humans.

In the last 100 years, there has accumulated a vast amount of information about the changes that accompany aging in a wide range of animal species. At the same time, there has been extensive documentation of the onset and characteristics of age-associated pathologies of humans and other mammals. It is argued that the totality of all this information is interrelated and provides a very extensive description of the deleterious changes in molecules, cells, tissues, and organs, which accompany both aging and many age-associated diseases. The accumulation of damage is in DNA, proteins, membranes, and organelles, as well as the formation of insoluble protein aggregates. The evolved design of many organ systems, such as the cardiovascular system, the brain, and the eye, are incompatible with indefinite survival. The eventual failure to maintain the integrity of tissues and organs is the end result of the multiple causes of aging.

Aged↗
PubMed2004

The multiple and irreversible causes of aging.

At the end of the 20th century, scientists have revealed the biological causes of aging, and why it is so widespread among animals. It has also become apparent why different mammalian species have very different longevities. Aging is accompanied by changes in a wide range of cells, tissues, and organs. These include damage in DNA, proteins, membranes, and organelles, as well as the accumulation of high molecular weight insoluble aggregates. The multiple phenotypic changes that accompany aging show that there must also be many different causes. The failure to maintain a steady-state level of damage is the result of a limit to the resources that can be used to preserve the integrity of the soma. For each species, there is a tradeoff between what is invested in reproduction and what is used to maintain its cells, tissues, and organs. The failure of maintenance is irreversible, although longevity may be modulated under certain circumstances, such as dietary restriction accompanied by a loss of fertility.

Aged↗
PubMed2003

The early years of molecular biology: personal recollections.

The early years of molecular biology were characterized by a strong interaction between theory and experiment. This included the elucidation of the structure of DNA itself; genetic fine structure, recombination and repair; DNA replication; template-directed protein synthesis; the universality of the triplet genetic code, and the co-linearity of the DNA sequence of structural genes and the sequence of amino acids in proteins. The principle of co-linearity was later modified when split genes were discovered. It is suggested that accurate splicing of gene transcripts might also be template directed. In 1958 Crick proposed a 'central dogma' of molecular biology stating that information could not be transmitted from proteins to DNA. Nevertheless, proteins can chemically modify DNA, and this is now known to have strong effects on gene expression.

Autobiographies as Topic↗
PubMed2002

Twenty years of ageing research at the Mill Hill laboratories.

Research on ageing was carried out in the Genetics Division laboratories, Mill Hill, London, from 1970 to 1990, resulting in more than 100 publications. The work centred around the in vitro ageing of human diploid fibroblasts, but there was also research on transformed cells, rat and mouse tissues, human lymphocytes, chick cells, mice and a microbial model system. The major conclusion from all this research, together with a broad overview of the whole field of gerontology, is that ageing has multiple causes, and that adult animals become senescent through the eventual failure of several important maintenance mechanisms.

Aging↗
PubMed2002

DNA methylation and epigenetic inheritance.

Mammalian cell lines silence genes at low frequency by the methylation of promoter sequences. These silent genes can be reactivated at high frequency by the demethylating agent 5-azacytidine (5-aza-CR). The inactive and active epigenetic states of such genes are stably inherited. A method for silencing genes is now available. It involves treatment of permeabilized cells with 5-methyl deoxycytidine triphosphate (5-methyl dCTP) which is incorporated into DNA. The methylation of promoter sequences has been confirmed using the bisulfite genomic sequencing procedure. Methylated oligonucleotides homologous to promoter sequences might be used to specifically target and silence given genes, but results so far have not been conclusive. Treatments that silence or reactivate genes by changing DNA methylation can be referred to as epimutagens, as distinct from mutagens that act by changing DNA sequences. The epimutagen 5-aza-CR reactivates genes but has little mutagenic activity, whereas standard mutagens (such as ethyl methane sulfonate and ultraviolet light) have little reactivation activity. Nevertheless, much more information is required about the effects of DNA-damaging agents in changing DNA methylation and gene activity and also about the role of epimutations in tumor progression.

Animals↗