Research People “Alzheimer’s is a modern-day plague. And it brings much the same fears as the contagions of old: every time someone of my generation forgets a word, we’re worried it’s the beginning of this dreadful disease...”
Alzheimer’s Adversary Beetles inspire ‘super-white’ new material
Chris Dobson: “As I See It...” Vignolini Group
It was a surprise to Professor Christopher Dobson, when he was studying the “totally innocent” antibacterial protein lysozyme, to learn it had been found deposited in clumps in the organs of some patients at a London clinic. He was intrigued and the puzzle led him into the study of protein aggregation and its relationship to human disease. Over the subsequent 25 years, the work by The ‘super-whiteness’ an Asian beetle has Chemistry researchers developin a new Chris and his research of group, colleagues andinspired collaborators has brought vitalto advances our material “twenty thirty times than common paper”. Thediseases researchers say it can help understanding ofto disorders suchwhiter as Parkinson’s and Alzheimer’s – and resulted in new approaches halting theand disorder he views a modern-day plague. improve theto appearance performance ofas a range of products from cosmetics to paints.
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This could be of interest to a wide range of consumer goods sectors. Manufacturers have been looking for new ways to enhance the whiteness of materials – from sun creams to toothpaste to paints – without using whitening agents that can affect consumers’ health or adversely impact the environment.
“And the research isn’t over yet,” says Olimpia. “We are hoping to do further research and to see if we can optimise this material even more.”
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As they describe in Advanced Materials, the research teams created these ultra-thin membranes using nanoscale cellulose fibres found naturally in wood pulp. This rate porous membrane material originally conceived The of aggregation can be was explosive. for use as a the chemical butwhose the Cambridge researchers We studied major filter, protein aggregation studied the way is carrieddisease in it and discovered is associated withlight Alzheimer’s and found that once it appears found that a fewextremely aggregateswhite. form,They they then catalyse thethat by adjustingofthe sizeaggregates and architecture nanoscale production more in a sortofofthe chain fibres within it, they could–tweak to produce different reaction. Tuomas Knowles then aitresearch fellow levels of whiteness, extremely to transparent. at St John’s and nowfrom a professor and white colleague in the Chemistry Department – played the key role They achieved this by ‘tuning’ porosityof ofthe their in enabling us to work out the the mechanism cellulose material, and adjusting its structure and the aggregation process, a really key breakthrough. packing of the scattering centres within it. They found that when the material has few pores, it does not scatter We’re looking at the protective mechanisms in the light so well because its appearance is uniform; when body. this happens, the material looks transparent. But we when ‘Molecular chaperones’ assist protein folding but a largethat number of pores embedded in it, light ‘sees’ found they also play are a key role in slowing down them as variations andamyloid is thus scattered, a the formation of these structures.producing We’re whitelooking colouration. now at ways to mimic these natural defence mechanisms artificially and so help protect the body The researchers the resulting against them for say a longer time. Myultra-thin colleaguematerial Michelehas a “whiteness twenty to thirty in times that of common Vendruscolo, also a Professor the department, has paper”.that Additionally, the new material’sinwhiteness also shown one can design antibodies a computer rivalsbind thattoofspecific materials that have higher that regions in themuch proteins andlightinhibit reflecting properties but cannot be manufactured in an the aggregation process. environmentally sustainable way. We’re finding ways to reverse the process. In the recently-established Centre for Misfolding
Olimpia Onelli.
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Diseases – that brings together the Dobson, Knowles and Vendruscolo groups and our associates and collaborators – we are developing strategies for combating such protein aggregation. We have found that small molecules, including drugs used to treat other diseases, can inhibit this process in the laboratory and in a model organism, the nematode worm. The hope is it will work in humans as well. And we’ve found other molecules able to suppress the aggregation of the proteins involved in Parkinson’s disease, one of which is now in clinical trials in the USA. The new Chemistry of Health building will help our work. We’re very lucky to have the new Chemistry of Health Building about to open, thanks to several extremely generous donations that made its construction possible. It will house the labs where we conduct fundamental science, as well as Wren Therapeutics – a drug discovery company founded to take our therapies into human Thepatients. research was undertaken through a collaboration between Dr Silvia Vignolini and PhD students Olimpia Onelli and Gianni Jacucci in
Cambridge, Professor Olli Ikkala and PhD student Matti Toivonen in Preventing andand treating Alzheimer’s disease and other Aalto University Finland. neurodegenerative conditions are huge challenges. We are, however, confident that this plague be defeated in due The funding for the Cambridge arm ofwill the research came from the European Council and a BBSRC David PhillipsinFellowship. course, just asResearch those plagues affecting humanity the past have largely been consigned to history.
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Alzheimer’s disease is a plague. Alzheimer’s disease is caused by protein malfunctions. cientists in the Department of Chemistry have explains: “Our eyes see whiteness when they are exposed The best-known plague, the Black Death, was an Everything that happens in our bodies is catalysed or controlled been studying the ‘super-white’ Cyphochilus to light that contains all the colours in the visible spectrum. infectious bacterial disease that devastated Europe in by proteins, of which we have around 100,000 different types. beetle for several years. Intrigued by the In nature, organisms like the beetle produce this effect by the 14th century. A more recent plague, the 1918-19 In order to function, most proteins have to fold into specific exceptional light-scattering properties of its having many non-uniform regions of their body – we call outbreak of Spanish Flu, was the biggest pandemic the structures. The cells in which they fold are highly complex scales, which make the beetle appear to be white them ‘scattering centres’ – that disperse the light randomly world has ever seen. Until now... environments and sometimes things go wrong. I have spent a lot even though its body is black, PhD student Olimpia Onelli and reflect it back at us from a variety of directions. When all of my career studying protein folding and we now know many of and her supervisor Dr Silvia Vignolini have been researching colours are scattered equally well, it appears white.” Alzheimer’s disease is a new ‘plague’, already affecting the general principles involved. More recently, initially because ways of creating a material that mimicked these properties. around 40 million people worldwide, a number predicted of the observation with lysozyme, I’ve become very interested But they were intrigued by the fact that the beetle’s scales to triple by 2050. It’s one of a group of non-infectious in protein misfolding that can give rise to disease. Some such And as they reported recently in the journal Advanced produce this effect despite being extremely thin. Usually diseases that terrifies us as it is currently completely diseases are caused by a shortage of properly functioning Materials, they have been successful. Inspired by the materials require a certain degree of thickness (typically incurable, largely untreatable and usually fatal. proteins, as in cystic fibrosis. Other diseases result because structures and properties of the insect’s scales, and using a few hundred microns) in order to have enough of these proteins misfold and end up in the wrong place in the body. natural materials, they have successfully created a new scattering centres to reflect the light and make it appear We havewhose only known about for a material whiteness “farAlzheimer’s exceeds thatdisease of common white. The beetle, however, is an intriguing exception to this And then there is a family of disorders – including Alzheimer’s century. paper”. The new material also has the benefit of being rule. “The Cyphochilus beetle’s scales are extremely thin – just disease, Type 2 diabetes, and Parkinson’s, Huntington’s and It was first Their reported 1906 by Dr by Alois Alzheimer. Hewith had ultra-thin. workinwas helped a collaboration one hundredth of the width of a human hair,” says Olimpia. motor neurone diseases – where misfolding causes proteins aresearchers 51-year-oldatfemale patient with what we now know Aalto University in Finland. “If you cut a sheet of paper as thin as that, it would be to clump together, giving rise to intractable deposits called was an early-onset form of the disease. Her husband transparent. But the beetle’s scales still appear very white.” amyloid fibrils. This process abolishes protein function, disrupts couldn’t afford to pay for heracare so he agreed that Lead author Silvia Vignolini, Reader here in the department, organs like the heart and generates cellular toxins. Alzheimer wouldpaves look after her for anddeveloping in return, Alzheimer says: “This work the way a viable To find out how the beetle achieves this effect, Silvia and her could analyse her brain when she died. large-scale method for producing white coatings that are co-authors used electron microscopy to study its scales. They Proteins naturally like to form these amyloid deposits. sustainable.” She and co-author Olimpia Onelli have already knew, from Prof Vukusic’s discovery, that the scales contain We discovered accidentally that in the laboratory perfectly As antibiotics, immunisation programmes improved patented the material and are now hopingand to license it for many scattering centres, but this research revealed that ordinary proteins can aggregate and form amyloid structures. hygiene have in greatly reduced diseases, it’s manufacture products suchinfectious as cosmetics. the structure works so efficiently because these scattering A postdoc who left his sample of an unfolded protein in an non-infectious conditions – such as heart disease, cancer centres are very densely packed in the scales without being NMR spectrometer over a long weekend discovered, on his and now Alzheimer’s – that challenge us. In the UK, it A survival mechanism overcrowded. return, that it had turned into a gel. We were curious about this already costs £30 billion a year care for people with For the Cyphochilus beetle, its to exceptional whiteness phenomenon and found that the NMR tube was full of amyloid Alzheimer’s disease. If no is treatments found, the (in proportion to its size) a survival are mechanism that Overcoming the challenge that we then thought were associated only with diseases. increasing number of people withfungi this disorder have It fibrils camouflages it among the white found inwill its habitat. It has long been thought that manufacturing an ultra-thin crippling impacts on society and has also been of great interest to economy scientists worldwide. since it was first synthetic material that could achieve the same degree of Then a graduate student made the remarkable observation that noted, by Prof Pete Vukusic at Exeter University, almost a whiteness as this was an insurmountable challenge. But the amyloid form of proteins can be thermodynamically much Why is Alzheimer’s disease increasing so rapidly? decade ago. inspired by these findings, the researchers have now made more stable than their functional forms. It was a real surprise It is due to the vast increase in the numbers of people extremely thin membranes that achieve a very bright to discover that many of our proteins would much rather be living into old age. At 65, our chances of getting The researchers knew that the key to the beetle’s whiteness whiteness despite being only a few microns thick. clumped together as aggregates and that they have an inherent Alzheimer’s disease are twoits in scales. a hundred. If we live lies in the interaction ofone lightorwith As Olimpia tendency to convert into this state. to 85, our chances of getting it are about one in three.
ISSUE 57 Spring 2018