The Croonian Lecture, 1980. The complex proteases of the complement system

The assembly and activation of the early components of complement, after their interaction with antibody-antigen complexes, are described in terms of the structures of the different proteins taking part. C1q, a molecule of unique half collagen--half globular structure, binds to the second constant domain of the antibody molecules through its six globular heads. A tetrameric complex of C1r2-C1s2 binds to the collagenous tails and leads to formation of the serine-type proteases C1r and C1s. C1s activates C4, which forms a covalent bond between its alpha' chain and the Fab section of the antibody. C2 is also activated by C1s and associates with the bound C4 molecule to form C42, a labile protease that activates C3, but which loses activity as the C2 peptide chains dissociate from C4. C2, by analogy with factor B, the equivalent component of the alternative pathway of activation, appears to be a novel type of serine protease with a similar catalytic site but different activation mechanism to the serine proteases that have been described previously.     

The Croonian Lecture 2004 risk: food, fact and fantasy

We all take risks, but most of the time we do not notice them. We are generally bad at judging the risks we take, and in the end, for some of us, this will prove fatal. Eating, like everything else in life, is not risk free. Is that next mouthful pure pleasure, or will it give you food poisoning? Will it clog your arteries as well as filling your stomach? This lecture weaves together three strands-the public understanding of science, the perception of risk and the role of science in informing government policy-as it explains how food risks are assessed and managed by government and explores the boundaries between the responsibilities of the individual and the regulator. In doing so, it draws upon the science of risk assessment as well as our attitudes to risk in relation to issues such as bovine spongiform encephalopathy, dioxins in salmon and diet and obesity.     

The Croonian Lecture, 1992. The key role of the thymus in the body's defence strategies.

For centuries the thymus has remained a mysterious organ with largely unknown functions. The first demonstration of its crucial role in the development of the immune system was reported in 1961, when it was found that mice thymectomized at birth had poorly developed lymphoid tissues, impaired immune reactivities, and an inordinate susceptibility to develop infections. Although thymus lymphocytes were for a long time deemed immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating to give rise to a progeny of cells which did not secrete antibody (T cells), but which had a remarkable ability to induce bone marrow cells (B cells) to become antibody formers. This was the first unequivocal demonstration of a major division of labour among mammalian lymphocytes. Tremendous progress in our understanding of the function of the thymus and of the T cells derived from it followed. Distinct T cell subsets were characterized and shown to have an essential role in initiating and regulating a variety of immune responses. The ontogenetic events which occurred during their differentiation were mapped, and this allowed studies of the selection of the T cell repertoire. The major histocompatibility complex and associated peptides were shown to govern T cell selection and antigen activation, and the antigen-specific T cell receptor and the genes which code for it were characterized. Future studies should allow some insight into how to activate T cells more effectively for vaccination purposes, and how to switch them off to prevent autoimmune reactions and to induce tolerance to transplanted tissues.     

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.     

The Florey Lecture, 1991. The colony-stimulating factors: discovery to clinical use.

The four colony-stimulating factors, GM-GSF, G-CSF, M-CSF and Multi-CSF, are specific glycoproteins with a likely common ancestral origin which interact to regulate the production, maturation and function of granulocytes and monocyte-macrophages. Each has been purified and produced in active recombinant form. Animal studies have shown the ability of injected CSF to increase the production and functional activity of granulocytes and macrophages in vivo and to enhance resistance to infections. These studies have led to the current extensive clinical use of CSFs to promote the formation and function of granulocytes and macrophages in a wide variety of disease situations in which there is an associated risk of serious infections. Although our knowledge of the control of haemopoiesis remains incomplete, the approaches used to develop the CSFs can be used to extend this knowledge, with the promise of the introduction into clinical medicine of additional effective therapeutic agents.     

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.     

The Leeuwenhoek Lecture, 1991. The influence of the host on microbes that cause disease.

Microbial pathogenicity or virulence, the capacity to cause disease, depends on microbial gene products that promote infection and penetration of mucous membranes, multiplication in the tissues, interference with host defence and sickness. Formation of these virulence determinants by microbes is influenced by the environment of the host, which differs from that in laboratory cultures. Studies of microorganisms grown in vivo, and of the host's influence on the production of virulence determinants, are increasing. In most studies, however, the complex conditions in vivo are not dissected to show the influence of particular factors. In future we should define specific host factors that are responsible for producing identified virulence determinants. There are three studies which point the way. Iron limitation in vivo causes production of bacterial siderophores, outer membrane receptors and some toxins. Erythritol, a growth stimulant for brucellae, causes intense placentitis and hence abortion in cattle, sheep and pigs. Cytidine 5'-monophospho-N-acetyl neuraminic acid (CMP-NANA) sialylates a conserved component of gonococcal lipopolysaccharide (LPS), thereby rendering gonococci in patients resistant to complement-mediated killing by serum. Although the lecture uses bacteria for examples, the principle applies equally to studies of viral and fungal pathogenicity.     

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.     

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.     

The Croonian lecture, 1988. Inositol lipids and calcium signalling

The response of cells to many external stimuli requires a decoding process at the membrane to transduce information into intracellular messengers. A major decoding mechanism employed by a variety of hormones, neurotransmitters and growth factors depends on the hydrolysis of a unique inositol lipid to generate two key second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Here I examine the second messenger function of Ins(1,4,5)P3 in controlling the mobilization of calcium. We know most about how this messenger releases calcium from internal reservoirs but less is known concerning the entry of external calcium. One interesting possibility is that Ins(1,4,5)P3 might function in conjunction with its metabolic product Ins(1,3,4,5)P4 to control calcium entry through a mechanism employing a region of the endoplasmic reticulum as a halfway house during the transfer of calcium from outside the cell into the cytoplasm. The endoplasmic reticulum interposed between the plasma membrane and the cytosol may function as a capacitor to insure against the cell being flooded with external calcium. When stimulated, cells often display remarkably uniform oscillations in intracellular calcium. At least two oscillatory patterns have been recognized suggesting the existence of separate mechanisms both of which may depend upon Ins(1,4,5)P3. In one mechanism, oscillations may be driven by periodic pulses of Ins(1,4,5)P3 produced by receptors under negative feedback control of protein kinase C. The other oscillatory mechanism may depend upon Ins(1,4,5)P3 unmasking a process of calcium-induced calcium release from the endoplasmic reticulum. The function of these calcium oscillations is still unknown. This Ins(1,4,5)P3/calcium signalling system is put to many uses during the life history of a cell.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Croonian lecture 2006. Structure of the living cell

The smallest viable unit of life is a single cell. To understand life, we need to visualize the structure of the cell as well as all cellular components and their complexes. This is a formidable task that requires sophisticated tools. These have developed from the rudimentary early microscopes of 350 years ago to a toolbox that includes electron microscopes, synchrotrons, high magnetic fields and vast computing power. This lecture briefly reviews the development of biophysical tools and illustrates how they begin to unravel the 'molecular logic of the living state'.