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PubMed1996

The Croonian Lecture, 1996: endogenous damage to DNA.

Although DNA is the carrier of stable genetic information, this giant molecule exhibits slow turnover in cells as a consequence of endogenous damage. DNA lesions result from hydrolysis, and from exposure to active oxygen and reactive metabolites. These major forms of damage to the heterocyclic bases and to the DNA backbone structure are now well characterized. Most DNA repair enzymes have apparently evolved to prevent genomic instability caused by endogenous lesions, the only exception being those that counteract ultraviolet light damage inflicted by the sun. Despite the efficiency of DNA repair pathways, some forms of endogenous DNA damage still cause mutagenic alterations and may result in human disease.

DNA Damage↗
PubMed1997

The Leeuwenhoek Lecture, 1997. Marek's disease herpesvirus: oncogenesis and prevention.

There are a number of neoplasias for which a herpesvirus is an essential part of the aetiology. Of these, Marek's disease is the most common and provides excellent opportunities for the study of a herpesvirus-induced tumour both experimentally and under natural conditions in the field. Marek's disease is caused by an alpha herpesvirus; it differs from the other oncogenic herpesviruses which are gamma herpesviruses. It is a ubiquitous virus in poultry populations of the world and is highly cell-associated and contagious, yet only a proportion of infected fowl develop tumours. Evidence is presented to suggest that at least one of the reasons for a wide variation in the incidence of the disease is a temporal interplay between virulent viruses and viruses of low or no virulence. The viral genes associated with the oncogenicity of Marek's disease virus (MDV) are discussed and it is concluded that it is likely that several genes are involved. Finally, a brief history of vaccination to control Marek's disease is given and mode of action discussed. It is concluded that the mechanism of protection is mainly through an antiviral cell mediated immune response, resulting in a lowered challenge virus burden. Marek's disease viruses over the past 40 years have been evolving greater oncogenicity, some of which are not adequately controlled by the vaccines that are currently available. It is suggested that for MDV to produce tumours, there is a need for the cytolytic infection phase and that infection must be with an MDV which possesses a functional gC, ICP4 for maintaining latency which allows the expression of at least the 1.8 kb family, pp38, meq, and possibly pp14 genes, for maintaining the tumour state and possibly initiating this state. Intervention in this process reduces the chance of tumour formation and incidence in a population which can occur through natural or man-mediated infection with non-pathogenic MDVs.

Animals↗
PubMed1998

The Croonian Lecture 1997. The phosphorylation of proteins on tyrosine: its role in cell growth and disease.

The reversible phosphorylation of tyrosines in proteins plays a key role in regulating many different processes in eukaryotic organisms, such as growth control, cell cycle control, differentiation cell shape and movement, gene transcription, synaptic transmission, and insulin action. Phosphorylation of proteins is brought about by enzymes called protein-tyrosine kinases that add phosphate to specific tyrosines in target proteins; phosphate is removed from phosphorylated tyrosines by enzymes called protein-tyrosine phosphatases. Phosphorylated tyrosines are recognized by specialized binding domains on other proteins, and such interactions are used to initiate intracellular signaling pathways. Currently, more than 95 protein-tyrosine kinases and more than 55 protein-tyrosine phosphatase genes are known in Homo sapiens. Aberrant tyrosine phosphorylation is a hallmark of many types of cancer and other human diseases. Drugs are being developed that antagonize the responsible protein-tyrosine kinases and phosphatases in order to combat these diseases.

Animals↗
PubMed1999

The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction.

Diabetes affects 3% of the European population and 140 million people worldwide, and is largely a disease of insulin resistance in which the tissues fail to respond to this hormone. This emphasizes the importance of understanding how insulin signals to the cell's interior. We have recently dissected a protein kinase cascade that is triggered by the formation of the insulin 'second messenger' phosphatidylinositide (3,4,5) trisphosphate (PtdIns (3,4,5)P3) and which appears to mediate many of the metabolic actions of this hormone. The first enzyme in the cascade is termed 3-phosphoinositide-dependent protein kinase-1 (PDK1), because it only activates protein kinase B (PKB), the next enzyme in the pathway, in the presence of PtdIns (3,4,5)P3. PKB then inactivates glycogen synthase kinase-3 (GSK3). PDK1, PKB and GSK3 regulate many physiological events by phosphorylating a variety of intracellular proteins. In addition, PKB plays an important role in mediating protection against apoptosis by survival factors, such as insulin-like growth factor-1.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1999

The Croonian Lecture 1999. Intracellular membrane traffic: getting proteins sorted.

The secretory and endocytic pathways within higher cells consist of multiple membrane-bound compartments, each with a characteristic composition, through which proteins move on their way to or from the cell surface. Sorting of proteins within this system is achieved by their selective incorporation into budding vesicles and the specific fusion of these with an appropriate target membrane. Cytosolic coat proteins help to select vesicle contents, while fusion is mediated by membrane proteins termed SNAREs present in both vesicles and target membranes. SNAREs are not the sole determinants of target specificity, but they lie at the heart of the fusion process. The complete set of SNAREs is known in yeast, and analysis of their locations, interactions and functions in vivo gives a comprehensive picture of the traffic routes and the ways in which organelles such as the Golgi apparatus are formed. The principles of protein and lipid sorting revealed by this analysis are likely to apply to a wide variety of eukaryotic cells.

Adenosine Triphosphatases↗
PubMed2000

The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission.

Communication in the nervous system takes place at chemical and electrical synapses, where neurotransmitter-gated ion channels, such as the nicotinic acetylcholine (ACh) receptor, and gap junction channels control propagation of electrical signals from one cell to the next. Newly developed electron crystallographic methods have revealed the structures of these channels trapped in open as well as closed states, suggesting how they work. The ACh receptor has large vestibules extending from the membrane which shape the ACh-binding pockets and facilitate selective transport of cations across a narrow membrane-spanning pore. When ACh enters the pockets it triggers a concerted conformational change that opens the pore by destabilizing a gate in the middle of the membrane made by a ring of pore-lining alpha-helical segmets. The alternative 'open' configuration of pore-lining segments reshapes the lumen and creates new surfaces, allowing the ions to pass through. The gap junction channel uses a similar structural mechanism, involving coordinated rearrangements of alpha-helical segments in the plane of the membrane, to open its pore.

Acetylcholine↗
PubMed2005

The Croonian Lecture 2001 hunting the antisocial cancer cell: MCM proteins and their exploitation.

Replicating large eukaryotic genomes presents the challenge of distinguishing replicated regions of DNA from unreplicated DNA. A heterohexamer of minichromosome maintenance (MCM) proteins is essential for the initiation of DNA replication. MCM proteins are loaded on to unreplicated DNA before replication begins and displaced progressively during replication. Thus, bound MCM proteins license DNA for one, and only one, round of replication and this licence is reissued each time a cell divides. MCM proteins are also the best candidates for the replicative helicases that unwind DNA during replication, but interesting questions arise about how they can perform this role, particularly as they are present on only unreplicated DNA, rather than clustered at replication forks. Although MCM proteins are bound and released cyclically from DNA during the cell cycle, higher eukaryotic cells retain them in the nucleus throughout the cell cycle. In contrast, MCMs are broken down when cells exit the cycle by quiescence or differentiation. We have exploited these observations to develop screening tests for the common carcinomas, starting with an attempt to improve the sensitivity of the smear test for cervical cancer. MCM proteins emerge as exceptionally promising markers for cancer screening and early diagnosis.

Biomarkers, Tumor↗
PubMed2005

The Leeuwenhoek Lecture 2000 the natural and unnatural history of methane-oxidizing bacteria.

Methane gas is produced from many natural and anthropogenic sources. As such, methane gas plays a significant role in the Earth's climate, being 25 times more effective as a greenhouse gas than carbon dioxide. As with nearly all other naturally produced organic molecules on Earth, there are also micro-organisms capable of using methane as their sole source of carbon and energy. The microbes responsible (methanotrophs) are ubiquitous and, for the most part, aerobic. Although anaerobic methanotrophs are believed to exist, so far, none have been isolated in pure culture. Methanotrophs have been known to exist for over 100 years; however, it is only in the last 30 years that we have begun to understand their physiology and biochemistry. Their unique ability to use methane for growth is attributed to the presence of a multicomponent enzyme system-methane monooxygenase (MMO)-which has two distinct forms: soluble (sMMO) and membrane-associated (pMMO); however, both convert methane into the readily assimilable product, methanol. Our understanding of how bacteria are capable of effecting one of the most difficult reactions in chemistry-namely, the controlled oxidation of methane to methanol-has been made possible by the isolation, in pure form, of the enzyme components.The mechanism by which methane is activated by sMMO involves abstraction of a hydrogen atom from methane by a high-valence iron species (FeIV or possibly FeV) in the hydroxylase component of the MMO complex to form a methyl radical. The radical combines with a captive oxygen atom from dioxygen to form the reaction product, methanol, which is further metabolized by the cell to produce multicarbon intermediates. Regulation of the sMMO system relies on the remarkable properties of an effector protein, protein B. This protein is capable of facilitating component interactions in the presence of substrate, modifying the redox potential of the diiron species at the active site. These interactions permit access of substrates to the hydroxylase, coupling electron transfer by the reductase with substrate oxidation and affecting the rate and regioselectivity of the overall reaction. The membrane-associated form is less well researched than the soluble enzyme, but is known to contain copper at the active site and probably iron. From an applied perspective, methanotrophs have enjoyed variable successes. Whole cells have been used as a source of single-cell protein (SCP) since the 1970s, and although most plants have been mothballed, there is still one currently in production. Our earlier observations that sMMO was capable of inserting an oxygen atom from dioxygen into a wide variety of hydrocarbon (and some non-hydrocarbon) substrates has been exploited to either produce value added products (e.g. epoxypropane from propene), or in the bioremediation of pollutants such as chlorinated hydrocarbons. Because we have shown that it is now possible to drive the reaction using electricity instead of expensive chemicals, there is promise that the system could be exploited as a sensor for any of the substrates of the enzyme.

Gene Expression Regulation, Bacterial↗
PubMed2005

The Ferrier Lecture 2004 what can transcranial magnetic stimulation tell us about how the brain works?

Transcranial magnetic stimulation (TMS) is a technique whereby parts of the cerebral cortex and underlying white matter can be excited by a brief electrical current induced by a similarly brief, rapidly fluctuating magnetic field which is itself produced by rapidly discharging a current through an insulated coil held against the scalp. When combined with magnetic resonance structural and functional images of the subject's brain, the stimulation can be directed at specific cortical areas. Over a period of only 15 years, TMS has revealed hitherto unsuspected aspects of brain function, such as the role of distant parts of the brain in recovery from stroke, and has helped to resolve several previously intractable disputes, such as the neuronal basis of conscious awareness. This article describes and discusses the origins and nature of TMS, its applications and limitations, and its especial usefulness in conjunction with other techniques of evaluating or imaging brain activity.

Awareness↗
PubMed2005

The Medawar Lecture 1998 is science dangerous?

The idea that science is dangerous is deeply embedded in our culture, particularly in literature, yet science provides the best way of understanding the world. Science is not the same as technology. In contrast to technology, reliable scientific knowledge is value-free and has no moral or ethical value. Scientists are not responsible for the technological applications of science; the very nature of science is that it is not possible to predict what will be discovered or how these discoveries could be applied. The obligation of scientists is to make public both any social implications of their work and its technological applications. A rare case of immoral science was eugenics. The image of Frankenstein has been turned by the media into genetic pornography, but neither cloning nor stem cells or gene therapy raise new ethical issues. There are no areas of research that are so socially sensitive that research into them should be proscribed. We have to rely on the many institutions of a democratic society: parliament, a free and vigorous press, affected groups and the scientists themselves. That is why programmes for the public understanding of science are so important. Alas, we still do not know how best to do this.

Cloning, Organism↗
PubMed2005

The Medawar Lecture 2004 the truth about science.

The attitudes of scientists towards the philosophy of science is mixed and includes considerable indifference and some hostility. This may be due in part to unrealistic expectation and to misunderstanding. Philosophy is unlikely directly to improve scientific practices, but scientists may find the attempt to explain how science works and what it achieves of considerable interest nevertheless. The present state of the philosophy of science is illustrated by recent work on the 'truth hypothesis', according to which, science is generating increasingly accurate representations of a mind-independent and largely unobservable world. According to Karl Popper, although truth is the aim of science, it is impossible to justify the truth hypothesis. According to Thomas Kuhn, the truth hypothesis is false, because scientists can only describe a world that is partially constituted by their own theories and hence not mind-independent. The failure of past scientific theories has been used to argue against the truth hypothesis; the success of the best current theories has been used to argue for it. Neither argument is sound.

Knowledge↗
PubMed2005

The Medawar Lecture 2001 knowledge for vision: vision for knowledge.

An evolutionary development of perception is suggested-from passive reception to active perception to explicit conception-earlier stages being largely retained and incorporated in later species. A key is innate and then individually learned knowledge, giving meaning to sensory signals. Inappropriate or misapplied knowledge produces rich cognitive phenomena of illusions, revealing normally hidden processes of vision, tentatively classified here in a 'periodic table'. Phenomena of physiology are distinguished from phenomena of general rules and specific object knowledge. It is concluded that vision uses implicit knowledge, and provides knowledge for intelligent behaviour and for explicit conceptual understanding including science.

Biological Evolution↗
PubMed2005

The Bernal Lecture 2004 Are low-frequency electromagnetic fields a health hazard?

Electric power is an essential commodity of the developed world, and is critical to the continuing progress of our technology-based society, as well as to the growth of less privileged societies. In contrast to its overwhelming benefits, there is a suspicion that the magnetic component of the electromagnetic fields (EMFs) associated with power distribution and electrical appliances has adverse health effects, especially a small increased incidence of childhood leukaemia. The possibility that environmental EMFs represent a health hazard has serious economic implications for government, the electricity industry and society, as well as raising several profound scientific challenges, including, in particular, biophysical mechanisms, experimental replication and scientific uncertainty. These challenges are explored in relation to the experiences of the EMF Biological Research Trust, a UK medical research charity which funds basic research on the biological effects of extremely low-frequency electromagnetic fields (ELF-EMFs). As judged from these experiences, at the present time there is no compelling experimental evidence that environmental ELF-EMFs induce biological responses.

Biophysical Phenomena↗
PubMed2005

The Ferrier Lecture 1995 behind the seen: the functional specialization of the brain in space and time.

The visual brain consists of many different visual areas, which are functionally specialized to process and perceive different attributes of the visual scene. However, the time taken to process different attributes varies; consequently, we see some attributes before others. It follows that there is a perceptual asynchrony and hierarchy in visual perception. Because perceiving an attribute is tantamount to becoming conscious of it, it follows that we become conscious of different attributes at different times. Visual consciousness is therefore distributed in time. Given that we become conscious of different visual attributes because of activity at different, functionally specialized, areas of the visual brain, it follows that visual consciousness is also distributed in space. Therefore, visual consciousness is not a single unified entity, but consists of many microconsciousnesses.

Animals↗
PubMed2006

The Ferrier Lecture 1998. The molecular biology of consciousness investigated with genetically modified mice.

The question is raised of the relevance of experimental work with the mouse and some of its genetically modified individuals in the study of consciousness. Even if this species does not go far beyond the level of 'minimal consciousness', it may be a useful animal model to examine the elementary building blocks of consciousness using the methods of molecular biology jointly with investigations at the physiological and behavioural levels. These building blocks which are anticipated to be universally shared by higher organisms (from birds to humans) may include: (i) the access to multiple states of vigilance, like wakefulness, sleep, general anaesthesia, etc.; (ii) the capacity for global integration of several sensory and cognitive functions, together with behavioural flexibility resulting in what is referred to as exploratory behaviour, and possibly a minimal form of intentionality. In addition, the contribution of defined neuronal nicotinic receptors species to some of these processes is demonstrated and the data discussed within the framework of recent neurocomputational models for access to consciousness.

Animals↗