The Rise of the Therapeutic State (The City in the Twenty-First Century Book Series)

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Further research on this system resulted in the discovery that these mutations greatly increased the probability of the protein misfolding, and that the misfolding process resulted in the conversion of the protein into pathogenic amyloid fibrils. The existence of a common architecture for proteins in amyloid fibrils contrasts strongly with the fact that the native states of proteins are extremely varied, forming intricate and complex folds that are determined by the sequence of the amino acid building blocks in the polypeptide chains of which they are composed.

Images of amyloid fibrils formed from the SH3 domain of PI3 kinase. The fibrils were formed in vitro by incubation of the protein whose native structure is represented in Fig. Comparison of examples of native and amyloid structures of protein molecules. On the left are ribbon diagrams of the native structures of three small proteins: an SH3 domain top , myoglobin bottom and acylphosphatase middle.

The protofilaments are held together by much weaker interactions involving primarily side-chain contacts. As the main chain is common to all polypeptides, the core protofilament structures of fibrils from different sequences have common features, differing only in detail as a result of differences in the non-dominant effects of side-chain packing. The black arrow indicates that when the native states of globular proteins are destabilised, they tend to convert into the generic amyloid structure, as described in the text.

From Dobson Structure of an amyloid fibril at atomic resolution. The structure shown is one of several polymorphs of the amyloid fibrils that are formed from an residue fragment of transthyretin Fitzpatrick et al. The combination of cryo-electron microscopy imaging a with solid-state NMR analysis has enabled the determination of an atomic-level structure b.

From Knowles et al. The conversion of soluble protein molecules into amyloid fibrils is accompanied by the loss of biological activity, as the latter is generated by the proximity of the functional groups of specific side-chains that are brought together in the unique fold of the native state.

The conversion of a protein into the amyloid states is, however, associated with more than a loss of biological activity. Biological systems have evolved in such a way that the correctly folded structures of protein molecules, and indeed other biological molecules, can be packed together at high densities within cells and extracellular space Minton The amyloid state of a protein molecule except in the rare cases where this form of proteins has a functional role is intrinsically misfolded, and so is inherently prone to interact inappropriately within the crowded and complex environment of a living system Dobson The assembly into amyloid fibrils is a stepwise process that begins with the formation of small clusters of misfolded protein molecules that ultimately grow into mature fibrils.

A key issue that arises in this context is why such species form and give rise to disease. Protein biosynthesis in living systems involves the generation of polypeptide chains having specific sequences of amino acids, the information for which is encoded in the genomic DNA, following which the folding process takes place in complex cellular environments. There is a finite possibility that any given chain will not fold correctly, but there are sophisticated and highly efficient systems within cells that can detect that a given polypeptide chain is misfolded and then target it for degradation; such a mechanism avoids the accumulation of potentially toxic aggregates, enables the component amino acids to be recycled and incorporated into new protein molecules, and in addition turns out to play a key role in the functioning of the immune system Dobson ; Rubinsztein The actions of molecular chaperones and other systems that prevent misfolding play a key role in the maintenance of protein homeostasis, the mechanism by which every living system maintains the appropriate balance of the generation and degradation of proteins that enables all the normal functions of the organism to be carried out.

Once such protective systems fail to prevent the progressive aggregation of one or more proteins, such homeostasis is lost and pathology results Balch et al. It is clear that the ability to avoid protein aggregation is an important factor in biological evolution, and that all our proteins are able to remain in their functional states under normal physiological conditions. Nevertheless, recent evidence indicates that most proteins within their biological environments are at the highest concentrations at which they can remain soluble Tartaglia et al. The reason for this situation is likely to result from the fact that the sequences and structures of protein molecules have evolved to enable them to be stable at the concentrations that are required for their optimal function.

As random mutations will in general reduce their stability and solubility, proteins in living systems will tend to be just capable of remaining in their functional states under normal conditions. This conclusion enables us, at least qualitatively, to be able to rationalise the reasons that protein misfolding diseases—virtually unknown a century ago—are now becoming frighteningly common Dobson ; Knowles et al.

Other misfolding disorders are associated with different features of modern life, for example increasing obesity can change the levels of crucial protein hormones in the pancreas and result in type II diabetes. The two right hand tubes are of peptides that contain mutations that decrease the propensity to form pre-fibrillar aggregates protofibrils in particular. The lower panel c shows the degree of correlation between the relative locomotor activity of a series of mutational variants against their predicted propensities to form protofibrils.

A summary of the general classes of mechanism that create protein aggregates.


Such aggregates can grow, and in the case of fibrillar species elongate, by the addition of further monomeric species. For further explanation see Cohen et al. Identification of the inhibition of secondary nucleation and evaluation of the consequences on the generation of toxic oligomers using kinetic analysis.

The dashed green lines show predictions for the resulting reaction profiles when each of a primary nucleation, b fibril elongation and c secondary nucleation is inhibited by the chaperone. Note the characteristic differences in the change in the shape of the reaction profile in each case. The prediction for the case where the chaperone solely and entirely suppresses secondary nucleation is matched essentially perfectly in the presence of excess Brichos.

The thin dotted lines in c are theoretical predictions for the intermediate Brichos concentrations using the association and dissociation rate constants determined from separate binding experiments Cohen et al.

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The blue line corresponds to the situation without the presence of Brichos and the dashed green lines show predictions when each of d primary nucleation, e fibril elongation and f secondary nucleation is inhibited by Brichos. The results show that this particular chaperone suppresses effectively completely the latter process that has been shown to be that responsible for the proliferation of toxic oligomeric species in the aggregation process in the absence of the chaperone. Adapted from Cohen et al. The fact that biology has managed to generate such effective protection mechanisms, that result in few cases of AD developing until old age except where pathogenic mutations act to increase the risk of misfolding and aggregation, suggests that we might learn from the strategies that have evolved in living systems.

The increasing emergence of misfolding diseases in the modern world, and indeed the experiments with fruit flies discussed above, show that relatively modest changes in the concentrations or properties of proteins are sufficient to cause a shift between health and disease. One particularly attractive therapeutic strategy, therefore, would be to find means of enabling our natural defence systems to continue to act effectively in old age.

We are therefore exploring ways of achieving this objective by searching for molecules that act, rather like the chaperones discussed above, as inhibitors of one or more of the microscopic processes that are involved in the aggregation process. Initial results suggest that small molecules that resemble existing types of pharmaceutical compounds may be able to act in this way Arioso et al.

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By contrast, the bacterial and viral diseases that once plagued humankind were studied for centuries in the context of the progressive developments in our understanding of biological and medical science Dobson Such diseases that were until recent times thought to be incurable are increasingly considered to be manageable and eminently treatable. Protective compounds such as statins reduce the risk of heart disease, and drugs such as tamoxifen have proved to be extremely effective in treating cancer. Although some advances in treatments over the ages have been fortuitous, the large majority has emerged through painstaking scientific study of the causes of the disease in question, followed by careful evaluation and development of therapeutic compounds that emerge from the testing and screening of possible lead compounds Dobson The pace of advances in all aspects of science and medicine has never been greater, and collaborative efforts that bring together experts in different disciplines to address major problems have never been more strongly encouraged.

We need to understand yet more about the details of the underlying causes of these conditions and we need to develop new biomarkers that enable the progression of disease to be monitored rigorously and regularly; the latter are essential to enable clinical trials to be carried out effectively and rapidly.

With the progress that is being made in such directions we can therefore be extremely optimistic that misfolding diseases will follow infectious diseases and illnesses such as cancer into conditions that can increasingly successfully be prevented and treated Dobson ; Knowles et al. In this manner dementia should be like the plagues of the past, in that its rapid rise in incidence will be followed by a steady decrease as it becomes a condition that can be managed effectively.

This article is focused particularly on the studies carried out by members of my own laboratory and our many collaborators. There are too many people for me to mention them all in this section, but I would like to thank in particular, however, my close colleagues in Cambridge, Professors Michele Vendruscolo and Tuomas Knowles, who have contributed an incalculable amount to the work described in this article.

Finally, I would like to thank my wife, Mary Dobson, not just for her unfailing love and support, but for all that she has taught me about the nature and history of disease, and for the constant inspiration of her own work and writings on these and many other topics.

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Skip to main content Skip to sections. Advertisement Hide. Download PDF. For socio-cultural anthropologists, the Cold War raised issues of race, war, genocide, counterinsurgency, and natural resources. We realized that anthropology was not an autonomous pursuit; instead, all of academia was embedded in politics. Anthropologists such as Hugh Gusterson and Joseph Masco began to write about nuclear laboratory cultures.

During a decade in which nuclear and alternative energy systems have played critical roles in world events, a wide-angled anthropology was a requirement. Anthropology has integrated holism, appreciation of history and the depth of time, and the consequences arising from how language frames thought. The discourse of energy specialists, for example, was rooted in models of growth that assumed an unlimited supply of natural resources and undervalued ecosystems.

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All of us were influenced by campus struggles in the and s over militarism, multi-national capitalism, scientific racism, and the politics of gender. But a larger question remains: What makes people human? Expanded funding in the four basic fields and in medical anthropology led to specializations and topical expertise. In socio-cultural anthropology, these include specializations in the law, politics, the economy, religion, ecology, medical issues, art, and education.

Credit goes to David Price, who singlehandedly examined the history of anthropology in its widest context in his book Anthropological Intelligence: The Deployment and Neglect of American Anthropology in the Second World War After all, our nationalities are reflected in the work we do. However, as anthropologists specialized, the concept of culture spread beyond the discipline to sociology, psychology, business schools, law schools, and beyond.

Culture as a concept was loose on the streets! We now have cultural sociology, cultural psychology, cultural geography, cultural law. Changes in the field, which included fascination with French philosophers such as Michel Foucault and Jacques Derrida and French anthropologist Pierre Bourdieu, stimulated vigorous critiques. Others used the changes to enrich ethnography.

Some call this global development theory. Because of all of this intellectual ferment, we now realize that anthropology has much to say about our own lives. Our ethnographies are written about the Shanghai stock market and the invention of derivatives on Wall Street. The anthropology of policy worlds is an emerging field that covers the politics of financialization, the rise of audit cultures and their impacts on culture and society, and the spread of diseases such as cholera epidemics.

Anthropologists are asking, for example, why some informants waste time with anthropologists and what exactly the collaborative engagement of anthropologists and subjects is in terms of ethics. New concerns with dichotomies of nature and culture led to studies of mythologies of menopause in Japan and North America and the pharmaceutical business.

Can menopause really be a disease if it happens to all women? Similar questions are asked of aging in India. Building on ethics and human rights issues are decades of research by Nancy Scheper-Hughes.

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In Death without Weeping , she addressed violence in everyday life and how violence and even death become normal and routine. She has made her work public by sharing with journalists wherever possible, testifying in court regarding crimes against humanity, and working hand in hand with Israeli colleagues. The work is multi-sited, sometimes conducting research undercover while examining criminal networks and transplant tourism.

Though power need not be the central theme for all anthropology, it is critical for understanding central dogmas. Our audiences are unpredictable.

Anthropologists who speak to a public wider than members of the discipline often have a greater immediate impact outside the discipline than in it. Grade schools regularly taught harmony ideology dispute-resolution and in global arenas lawyers were up against new international negotiators selling psychology rather than the rule of law. If we remain ignorant of debates outside of academia, we will increasingly find ourselves talking mainly to each other, trapped in a diminished space and working in cramped quarters.