̽��ֱ�� of Cambridge - David Klenerman

Scientists identify the cause of Alzheimer’s progression in the brain

sc604 — Fri, 29 Oct 2021 18:00:23 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, found that instead of starting from a single point in the brain and initiating a chain reaction which leads to the death of brain cells, Alzheimer’s disease reaches different regions of the brain early. How quickly the disease kills cells in these regions, through the production of toxic protein clusters, limits how quickly the disease progresses overall.

̽��ֱ��researchers used post-mortem brain samples from Alzheimer’s patients, as well as PET scans from living patients, who ranged from those with mild cognitive impairment to those with late-stage Alzheimer’s disease, to track the aggregation of tau, one of two key proteins implicated in the condition.

In Alzheimer’s disease, tau and another protein called amyloid-beta build up into tangles and plaques – known collectively as aggregates – causing brain cells to die and the brain to shrink. This results in memory loss, personality changes and difficulty carrying out daily functions.

By combining five different datasets and applying them to the same mathematical model, the researchers observed that the mechanism controlling the rate of progression in Alzheimer’s disease is the replication of aggregates in individual regions of the brain, and not the spread of aggregates from one region to another.

̽��ֱ��results, reported in the journal Science Advances, open up new ways of understanding the progress of Alzheimer’s and other neurodegenerative diseases, and new ways that future treatments might be developed.

For many years, the processes within the brain which result in Alzheimer’s disease have been described using terms like ‘cascade’ and ‘chain reaction’. It is a difficult disease to study, since it develops over decades, and a definitive diagnosis can only be given after examining samples of brain tissue after death.

For years, researchers have relied largely on animal models to study the disease. Results from mice suggested that Alzheimer’s disease spreads quickly, as the toxic protein clusters colonise different parts of the brain.

“ ̽��ֱ��thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s first author. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”

This is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade which allows the processes of aggregation and spread in the brain to be modelled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.

“This research shows the value of working with human data instead of imperfect animal models,” said co-senior author Professor Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see the progress in this field – fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”

̽��ֱ��researchers found that the replication of tau aggregates is surprisingly slow – taking up to five years. “Neurons are surprisingly good at stopping aggregates from forming, but we need to find ways to make them even better if we’re going to develop an effective treatment,” said co-senior author Professor Sir David Klenerman, from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge. “It’s fascinating how biology has evolved to stop the aggregation of proteins.”

̽��ֱ��researchers say their methodology could be used to help the development of treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s disease.

“ ̽��ֱ��key discovery is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied,” said Knowles.

̽��ֱ��researchers are now planning to look at the earlier processes in the development of the disease, and extend the studies to other diseases such as Frontal temporal dementia, traumatic brain injury and progressive supranuclear palsy where tau aggregates are also formed during disease.

̽��ֱ��study is a collaboration between researchers at the UK Dementia Research Institute, the ̽��ֱ�� of Cambridge and Harvard Medical School. Funding is acknowledged from Sidney Sussex College Cambridge, the European Research Council, the Royal Society, JPB Foundation, the Rainwater Foundation, the NIH, and the NIHR Cambridge Biomedical Research Centre which supports the Cambridge Brain Bank.

Reference:
Georg Meisl et al. ‘In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease.’ Science Advances (2021). DOI: 10.1126/sciadv.abh1448

For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. Their results could have important implications for the development of potential treatments.

This research shows the value of working with human data instead of imperfect animal models

Tuomas Knowles

National Institute of Mental Health, National Institutes of Health, USA

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Four Cambridge researchers recognised in the 2022 Breakthrough Prizes

sc604 — Thu, 09 Sep 2021 11:59:47 +0000

Professors Shankar Balasubramanian and David Klenerman, from Cambridge’s Yusuf Hamied Department of Chemistry, have been awarded the 2022 Breakthrough Prize in Life Sciences – the world’s largest science prize – for the development of next-generation DNA sequencing. They share the award with Pascal Mayer, from the French company Alphanosos.

In addition, Professor Suchitra Sebastian, from the Cavendish Laboratory, and Professor Jack Thorne, from the Department of Pure Mathematics and Mathematical Statistics, have been recognised with the New Horizons Prize, awarded to outstanding early-career researchers.

Professor Suchitra Sebastian has been awarded the 2022 New Horizons in Physics Prize for high precision electronic and magnetic measurements that have profoundly changed our understanding of high temperature superconductors and unconventional insulators.

Professor Jack Thorne has been awarded the 2022 New Horizons in Mathematics Prize, for transformative contributions to diverse areas of algebraic number theory, and in particular for the proof, in collaboration with James Newton, of the automorphy of all symmetric powers of a holomorphic modular newform.

Professors Balasubramanian and Klenerman co-invented Solexa-Illumina Next Generation DNA Sequencing (NGS), technology that has enhanced our basic understanding of life, converting biosciences into ‘big science’ by enabling fast, accurate, low-cost and large-scale genome sequencing – the process of determining the complete DNA sequence of an organism’s make-up. They co-founded the company Solexa to make the technology available to the world.

̽��ֱ��benefits to society of rapid genome sequencing are huge. ̽��ֱ��almost immediate identification and characterisation of the virus which causes COVID-19, rapid development of vaccines, and real-time monitoring of new genetic variants would have been impossible without the technique Balasubramanian and Klenerman developed.

̽��ֱ��technology has had – and continues to have – a transformative impact in the fields of genomics, medicine and biology. One measure of the scale of change is that it has allowed a million-fold improvement in speed and cost when compared to the first sequencing of the human genome. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars: today, the human genome can be sequenced in a single day at a cost of less than $1,000. More than a million human genomes are sequenced at scale each year, thanks to the technology co-invented by Professors Balasubramanian and Klenerman, meaning we can understand diseases much better and much more quickly. Earlier this year, they were awarded the Millennium Technology Prize. Balasubramanian is also based at the Cancer Research UK Cambridge Institute, and is a Fellow of Trinity College. Klenerman is a Fellow of Christ's College.

Professor Sebastian’s research seeks to discover exotic quantum phases of matter in complex materials. Her group’s experiments involve tuning the co-operative behaviour of electrons within these materials by subjecting them to extreme conditions including low temperature, high applied pressure, and intense magnetic field.

Under these conditions, her group can take materials that are quite close to behaving like a superconductor – perfect, lossless conductors of electricity – and ‘nudge’ them, transforming their behaviour.

“I like to call it quantum alchemy – like turning soot into gold,” Sebastian said. “You can start with a material that doesn’t even conduct electricity, squeeze it under pressure, and discover that it transforms into a superconductor. Going forward, we may also discover new quantum phases of matter that we haven’t even imagined.”

In addition to her physics research, Sebastian is also involved in theatre and the arts. She is Director of the Cavendish Arts-Science Project, which she founded in 2016. ̽��ֱ��programme has been conceived to question and explore material and immaterial universes through a dialogue between the arts and sciences.

“Being awarded the New Horizons Prize is incredibly encouraging, uplifting and joyous,” said Sebastian. “It recognises a discovery made by our team of electrons doing what they're not supposed to do. It's gone from the moment of elation and disbelief at the discovery, and then trying to follow it through, when no one else quite thinks it’s possible or that it could be happening. It’s been an incredible journey, and having it recognised in this way is incredibly rewarding.”

Professor Jack Thorne is a number theorist in the Department of Pure Mathematics and Mathematical Statistics. One of the most significant open problems in mathematics is the Riemann Hypothesis, which concerns Riemann’s zeta function. Today we know that the zeta function is intimately tied up with questions concerning the statistical distribution of prime numbers, such as how many prime numbers there are, how closely they can be found on the number line. A famous episode in the history of the Riemann Hypothesis is Freeman Dyson’s observation that the zeroes of the zeta function appear to obey statistical laws arising from the theory of random matrices, which had first been studied in theoretical physics.

In 1916, during his time in Cambridge, Ramanujan wrote down an analogue of the Riemann zeta function, inspired by his work on the number of ways of expressing a given number as a sum of squares (a problem with a rich classical history), and made some conjectures as to its properties, which have turned out to be related to many of the most exciting developments in number theory in the last century. Actually, there are a whole family of zeta functions, the properties of which control the statistics of the sums of squares problem. Thorne's work, recognised in the prize citation, essentially shows for Ramanujan’s zeta functions what Riemann proved for his zeta function in 1859.

Taking a broader view, Ramanujan’s zeta functions are now seen to fit into the framework of the Langlands Program. This is a series of conjectures, made by Langlands in the 1960’s, which have been described as a “grand unified theory of mathematics”, and which can be used to explain any number of phenomena in number theory. Another famous example is Wiles proof, in 1994, of Fermat’s Last Theorem. Nowadays the essential piece of Wiles’ work is seen as progress towards a small part of the Langlands program. Thorne's work establishes part of Langlands’ conjectures for a class of objects including Ramanujan’s Delta function.

"I am deeply honoured to be awarded the New Horizons Prize for my work in number theory," said Thorne. "Number theory is a subject with a rich history in Cambridge and I feel very fortunate to be able to make my own contribution to this tradition."

For the tenth year, the Breakthrough Prize recognises the world’s top scientists. Each prize is US $3 million and presented in the fields of Life Sciences, Fundamental Physics (one per year) and Mathematics (one per year). In addition, up to three New Horizons in Physics Prizes, up to three New Horizons in Mathematics Prizes and up to three Maryam Mirzakhani New Frontiers Prizes are given out to early-career researchers each year, each worth US $100,000. ̽��ֱ��Breakthrough Prizes were founded by Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki.

Four ̽��ֱ�� of Cambridge researchers – Professors Shankar Balasubramanian, David Klenerman, Suchitra Sebastian and Jack Thorne – have been recognised by the Breakthrough Prize Foundation for their outstanding scientific achievements.

L-R: Millennium Technology Prize, Nick Saffell, Jack Thorne

L-R: David Klenerman, Shankar Balasubramanian, Suchitra Sebastian, Jack Thorne

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Cambridge researchers awarded the Millennium Technology Prize

sc604 — Tue, 18 May 2021 14:32:48 +0000

̽��ֱ�� of Cambridge chemists Shankar Balasubramanian and David Klenerman have been jointly awarded the 2020 Millennium Technology Prize, one of the world’s most prestigious science and technology prizes, by Technology Academy Finland (TAF).

̽��ֱ��global prize, awarded at two-year intervals since 2004 to highlight the impact of science and innovation on society, is worth €1 million. Of the nine previous winners of the Millennium Technology Prize, three have subsequently gone on to win a Nobel Prize. This is the first time that the prize has been awarded to more than one recipient for the same innovation, celebrating the significance of collaboration. ̽��ֱ��announcement of the 2020 award was delayed due to the COVID-19 pandemic.

̽��ֱ��technology has had – and continues to have – a transformative impact in the fields of genomics, medicine and biology. One measure of the scale of change is that it has allowed a million-fold improvement in speed and cost when compared to the first sequencing of the human genome. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars: today, the human genome can be sequenced in a single day at a cost of $1,000. More than a million human genomes are sequenced at scale each year, thanks to the technology co-invented by Professors Balasubramanian and Klenerman, meaning we can understand diseases much better and much more quickly.

Professor Sir Shankar Balsubramanian FRS from the Yusuf Hamied Department of Chemistry, Cancer Research UK Cambridge Institute and a Fellow of Trinity College, said: “I am absolutely delighted at being awarded the Millennium Technology Prize jointly with David Klenerman, but it’s not just for us, I’m happy on behalf of everyone who has contributed to this work.”

Professor Sir David Klenerman FMedSci FRS from the Yusuf Hamied Department of Chemistry, and a Fellow of Christ’s College, said: “It’s the first time that we’ve been internationally recognised for developing this technology. ̽��ֱ��idea came from Cambridge and was developed in Cambridge. It’s now used all over the world, so I’m delighted largely for the team of people who worked on this project and contributed to its success.”

Next-generation sequencing involves fragmenting sample DNA into many small pieces that are immobilized on the surface of a chip and locally amplified. Each fragment is then decoded on the chip, base-by-base, using fluorescently coloured nucleotides added by an enzyme. By detecting the colour-coded nucleotides incorporated at each position on the chip with a fluorescence detector – and repeating this cycle hundreds of times – it is possible to determine the DNA sequence of each fragment.

̽��ֱ��collected data is then analysed using computer software to assemble the full DNA sequence from the sequence of all these fragments. ̽��ֱ��NGS method’s ability to sequence billions of fragments in a parallel fashion makes the technique fast, accurate and cost-efficient. ̽��ֱ��invention of NGS was a revolutionary approach to the understanding of the genetic code in all living organisms.

Next-generation sequencing provides an effective way to study and identify new coronavirus strains and other pathogens. With the emergence of the COVID-19 pandemic, the technology is now being used to track and explore mutations in the coronavirus. This work has helped the creation of multiple vaccines now being administered worldwide and is critical to the creation of new vaccines against new dangerous viral strains. ̽��ֱ��results will also be used to prevent future pandemics.

̽��ֱ��technology is also allowing scientists and researchers to identify the underlying factors in individuals that contribute to their immune response to COVID-19. This information is essential to unravelling the reason behind why some people respond much worse to the virus than others.

NGS technology has revolutionised global biological and biomedical research and has enabled the development of a broad range of related technologies, applications and innovations. Due to its efficiency, NGS is widely adopted in healthcare and diagnostics, such as cancer, rare diseases, infectious medicine, and sequencing-based non-invasive prenatal testing.

It is increasingly used to define the genetic risk genes for patients with a rare disease and to define new drug targets for disease in defined patient groups. NGS has also contributed to the creation of new and powerful biological therapies like antibodies and gene therapies.

In the field of cancer, NGS is becoming the standard analytical method for defining personalised therapeutic treatment. ̽��ֱ��technology has dramatically improved our understanding of the genetic basis of many cancers and is often used both for clinical tests for early detection and diagnostics both from tumours and patients’ blood samples.

In addition to medical applications, NGS has also had a major impact on all of biology as it allows the clear identification of thousands of organisms in almost any kind of sample, which is important for agriculture, ecology and biodiversity research.

Academy Professor Päivi Törmä, Chair of the Millennium Technology Prize Selection Committee, said: “ ̽��ֱ��future potential of NGS is enormous and the exploitation of the technology is still in its infancy. ̽��ֱ��technology will be a crucial element in promoting sustainable development through personalisation of medicine, understanding and fighting killer diseases, and hence improving the quality of life. Professor Balasubramanian and Professor Klenerman are worthy winners of the prize.”

Professor Marja Makarow, Chair of Technology Academy Finland said: “Collaboration is an essential part of ensuring positive change for the future. Next Generation Sequencing is the perfect example of what can be achieved through teamwork and individuals from different scientific backgrounds coming together to solve a problem.

“ ̽��ֱ��technology pioneered by Professor Balasubramanian and Professor Klenerman has also played a key role in helping discover the coronavirus’s sequence, which in turn enabled the creation of the vaccines – itself a triumph for cross-border collaboration – and helped identify new variants of COVID-19.”

Tomorrow (19 May 2021) Professors Balasubramanian and Klenerman will deliver the Millennium Technology Prize Lecture, talking about their innovation, at 14:30 at the Millennium Innovation Forum. ̽��ֱ��lecture can be accessed here.

British duo Professor Shankar Balasubramanian and Professor David Klenerman have been awarded the Millennium Technology Prize for their development of revolutionary DNA sequencing techniques.

Journeys of Discovery: Rapid genome sequencing

Millennium Technology Prize

David Klenerman and Shankar Balasubramanian receiving the MTP prize

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Journeys of discovery: rapid genome sequencing

lw355 — Tue, 18 May 2021 14:24:34 +0000

David Klenerman and Shankar Balasubramanian talk about their discovery of a revolutionary DNA sequencing technology – and the global impact that continues to surprise them.

Cambridge in the 2019 New Year honours list

plc32 — Fri, 28 Dec 2018 22:31:00 +0000

Professor David Klenerman, FRS was knighted for Services to Science and for the Development of High Speed DNA Sequencing Technology.

Professor Klenerman said: “I feel very humbled to be recognised in this way.”

Sir David is a professor of biophysical chemistry at the Department of Chemistry at the ̽��ֱ�� of Cambridge and a Fellow of Christ's College. He is best known for his contribution in the field of next-generation sequencing of DNA, which subsequently resulted in Solexa, a high-speed DNA sequencing company that he co-founded.

“I also want to acknowledge and sincerely thank the highly talented people who have worked with me over the years and without whom my research would simply not have been possible. In particular the development of Solexa sequencing was the result of a massive team effort.”

Klenerman was educated at the ̽��ֱ�� of Cambridge where he was an undergraduate student of Christ's College and received his Bachelor of Arts degree in 1982. He earned his Doctor of Philosophy degree in chemistry in 1986 as a postgraduate student of Churchill College.

Sir David has received a string of honours for his work, including a 2018 Royal Medal from the Royal Society for his outstanding contribution to applied sciences. He was elected as a Fellow of the Academy of Medical Sciences in 2015 and Fellow of the Royal Society in 2012.

Professor Madeleine Julia Atkins, who was first honoured as a CBE in 2011, has been promoted DBE for her Services to Higher Education.

Dame Madeleine, lately Chief Executive of the Higher Education Funding Council for England, has had a long and distinguished career in higher education, most recently providing outstanding leadership in ensuring a smooth transition between HEFCE and the new Office for Students and Research England. She has also been a Trustee and Board member for Nesta, and was until recently a Deputy Lieutenant in the West Midlands. She has been a Pro-Vice-Chancellor at Newcastle ̽��ֱ��, is a former Vice-Chancellor of Coventry ̽��ֱ��, and is now President of Lucy Cavendish College here at Cambridge ̽��ֱ��. She studied for a degree in law and history at Girton College and has a PhD from the ̽��ֱ�� of Nottingham.

Dame Madeleine said: “I am honoured to receive this award, which recognises the contribution of my former colleagues at HEFCE who worked so hard to make the transition to OfS and Research England both smooth and successful. I am delighted now to be bringing some of my experience in the higher education sector to support the students and Fellowship of Lucy Cavendish College”.

Professor John Frederick William Birney, FRS, the joint director, European Bioinformatics Institute was awarded a CBE For Services to Computational Genomics and to Leadership across the Life Sciences.

Professor Birney is Director of EMBL-EBI, Europe's flagship laboratory for the life sciences, and runs a small research group. He played a vital role in annotating the genome sequences of human, mouse, chicken and several other organisms. He led the analysis group for the ENCODE project, which is defining functional elements in the human genome. Birney’s main areas of research include functional genomics, assembly algorithms, statistical methods to analyse genomic information (in particular information associated with individual differences) and compression of sequence information.

Professor Birney, known as Ewan to his friends, family and colleagues, was educated at Eton, Oxford and St John’s College, Cambridge.

Dr Jennifer Mary Schooling, Director of the Centre for Smart Infrastructure and Construction (CSIC), ̽��ֱ�� of Cambridge was awarded an OBE For Services to Engineering and to Digital Construction.

Dr Schooling is a Fellow of Darwin College and has been the Director of CSIC since April 2013. CSIC focuses on how better data and information from a wide range of sensing systems can be used to improve our understanding of our infrastructure, leading to better design, construction and management practices. CSIC has strong collaborations with industry, developing and demonstrating innovations on real construction and infrastructure projects, and developing standards and guidance to enable implementation. Dr Schooling is also Chair of the Research Strategy Steering Group for the newly formed Centre for Digital Built Britain. Dr Schooling is founding Co-Editor-in-Chief of the Smart Infrastructure and Construction Proceedings journal (ICE). She recently served as a member of PAS185 smart cities security standard steering group and of ICE’s State of the Nation 2017 ‘Digital Transformation’ Steering Group. Prior to joining CSIC, Dr Schooling worked for Arup, leading the firm’s Research Business, and before that for Edwards Vacuum (then BOC Edwards) as a manager for New Product Introductions. She has a PhD from the ̽��ֱ�� of Cambridge.

Andrew Nairne, Director of Kettle’s Yard, was awarded an OBE for Services to Museums and the Arts. Kettle’s Yard is the ̽��ֱ�� of Cambridge’s modern and contemporary art gallery.

Andrew Nairne said: “I am delighted to receive this recognition following the hugely successful reopening of Kettle’s Yard in 2018: a magnificent team effort.”

“As Director of one of the eight ̽��ֱ�� of Cambridge Museums, I believe museums have a vital role to play in the life of both the ̽��ֱ�� and the community.”

̽��ֱ��Honours list, which dates back to around 1890, recognises notable services and contributions to Britain.

Members of collegiate Cambridge recognised for outstanding contributions to society in science, education, engineering and art

“I feel very humbled to be recognised in this way.”

Professor Sir David Klenerman

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̽��ֱ��Academy of Medical Sciences announces new Fellows for 2015

jeh98 — Mon, 11 May 2015 09:38:09 +0000

Forty-eight researchers from across the UK, including five Cambridge ̽��ֱ�� academics, have been recognised for their contribution to the advancement of medical science by election to the Fellowship of the Academy of Medical Sciences.

Academy Fellows are elected for excellence in medical research, for innovative application of scientific knowledge or for their conspicuous service to healthcare. ̽��ֱ��expertise of the new Fellows includes addictions, anaesthesia, age-related diseases and animal biology.

̽��ֱ��Fellows elected from the ̽��ֱ�� of Cambridge are:

Professor Roger Barker – Professor of Clinical Neuroscience and Honorary Consultant Neurologist, Addenbrooke’s Hospital and Department of Clinical Neurosciences

Professor Sarah Bray – Professor of Developmental Biology, Department of Physiology, Development and Neuroscience

Professor John Danesh – BHF Professor of Epidemiology and Medicine and Head of the Department of Public Health and Primary Care

Professor Fiona Gribble – Professor of Endocrine Physiology, Department of Clinical Biochemistry

Professor David Klenerman – Professor of Biophysical Chemistry, Department of Chemistry

Professor Sir John Tooke PMedSci, President of the Academy of Medical Sciences said: “ ̽��ֱ��Academy of Medical Sciences champions the excellence and diversity of medical science in the UK, and this is clearly demonstrated in this year’s cohort of new Fellows. Their broad range of expertise and fantastic achievements to date shows just how strong the Fellowship is – from the NHS knowledge of Sir Andrew Dillon to the policy experience of Professor Christl Donnelly. Their election is a much deserved honour, and I know they will contribute greatly to the Academy. I am delighted to welcome them all to the Fellowship, and look forward to working with them in the future.”

̽��ֱ��independent Academy of Medical Sciences promotes advances in medical science and campaigns to ensure these are translated into benefits for patients. ̽��ֱ��Academy’s Fellows are the United Kingdom’s leading medical scientists from hospitals, academia, industry and the public service.

View the full list of new Fellows.

̽��ֱ��Academy of Medical Sciences has announced the election of its new Fellows, including five Cambridge ̽��ֱ�� academics.

̽��ֱ��Academy of Medical Sciences

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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̽��ֱ��super-resolution revolution

lw355 — Fri, 27 Feb 2015 09:30:07 +0000

There has been a revolution in optical microscopy and it’s been 350 years in the making. Ever since Robert Hooke published his Physiological Descriptions of Minute Bodies in 1665, the microscope has opened up the world in miniature. But it has also been limited by the wavelength of light.

Anything smaller than the size of a bacterial cell (around 250 nanometres) appears as a blurred blob through an optical microscope, simply because light waves spread when they are focused on a tiny spot. As a result, resolving two tiny spots that lie close together has been tantalisingly out of reach using an optical microscope. Unfortunately, many biological interactions occur at a spatial scale much smaller than this.

But, thanks to recent breakthroughs, a new era of super-resolution microscopy has begun. ̽��ֱ��developments earned inventors Eric Betzig and William E Moerner (USA) and Stefan Hell (Germany) the 2014 Nobel Prize for Chemistry, and are based on clever physical tricks that work around the problem of light diffraction.

Professor Clemens Kaminski, whose team in the Department of Chemical Engineering and Biotechnology designs and builds super-resolution microscopes to study Alzheimer’s disease, explained: “ ̽��ֱ��technology is based on a conceptual change, a different way of thinking about how we resolve tiny structures. By imaging blobs of light at separate points in time, we are able to discriminate them spatially, and thus prevent image blur.”

Imagine taking a photo of a tree lit by the glow of ten thousand tiny lights scattered over its branches. ̽��ֱ��emission from each light would overlap. At best you would see a fuzzy, glowing shape lacking in detail. But if you were to switch on only a few lights at a time, locate the centre of each glow and take a picture, and then repeat this process thousands of times for different lights, the composite image would resolve into a myriad of distinguishable dots, denoting the exact position of each individual light on the tree.

This is analogous to the techniques developed by the Nobel Prize winners: in one technique, a sample is tagged with light-activated markers called fluorophores that can be switched on and off with pulses of light, like a switchable light bulb; in another, the light at the outer edges of each blob of light is selectively blocked.

Either way, by imaging a sparse subset of lights, they can be localised with nanometre precision. When combined, a picture starts to emerge that features a resolution that is 10 to 100 times better than previously possible.

“It’s been hailed as revolutionary because it means that biologists can validate some of their hypotheses for the first time,” said Dr Kevin O’Holleran who co-leads the Cambridge Advanced Imaging Centre (CAIC), which is currently building two super-resolution microscopes. “Although electron microscopy has very high resolution, it can’t be performed on live cells. With super-resolution optical microscopy, scientists can track molecular processes as they happen and in three dimensions.”

Meanwhile, Dr Steven Lee and Professor David Klenerman in the Department of Chemistry have built what they believe is the first 3D super-resolution microscope of its kind in Europe. They are using the machine to watch the organisation of cell-surface proteins at the point when an immune cell is triggered into action. Before super-resolution, they needed to artificially reduce the number of proteins on the cell surface to make visualisation easier; now, they can work with normal levels of up to 10,000 proteins at a time on the cell surface.

“These exciting discoveries have emerged through years of painstaking research by physical scientists trying to better understand how light interacts with matter at a fundamental level,” explained Lee. “This work has enabled us to gain insight into biological processes by simply ‘looking’ at dynamic events at spatial scales that much better approximate the physical dimension that biomolecules interact on.”

Kaminski’s team has been visualising the ultrastructure of the clumps of misfolded proteins that cause Alzheimer’s disease. “We’d like to study what causes proteins to become toxic when they aggregate, and visualise them as they move from cell to cell to see whether there are opportunities early in the process to halt their progression.”

Like any fast-moving and transformative technology, super-resolution microscopy has required researchers to drive forward the capabilities of the lenses and light sources, as well as the chemistry of the fluorophores and the mathematical algorithms for image analysis. As a result, designing and building their own microscopes, rather than waiting for commercial devices to become available, has been the best option.

“ ̽��ֱ��field is dynamic and no instrument is exactly right for the questions you want to answer. We have to build the instrument around the science,” explained Dr George Sirinakis, who works with Professor Daniel St Johnston in the Gurdon Institute. His machines will be used to understand cell polarity and visualise the movement of thousands of tiny sacs called vesicles as they transport their cargo within cells. This process has never been seen before because the vesicles are so small and move fast.

No longer are these benchtop machines. Super-resolution microscopes resemble an army of lenses and mirrors marching across a table top, each minutely turning, concentrating and shaping the light beam that falls onto the sample stained with fluorescence markers. Tens of thousands of images are collected from any one sample – creating a deluge of ‘big data’ that requires complex mathematical algorithms to make sense of the information.

Quite simply, super-resolution microscopy is a feat of engineering, physics, chemistry, mathematics, computer science and biology, and it’s therefore out of reach to researchers who lack the necessary expertise or funds to take a step into this field.

CAIC has recently been created to meet super-resolution and other microscopy needs in the biological sciences. “We are a research and development facility. We have state-of-the- art commercial microscopes and we build our own, tailoring them to the needs of the biologists who come to us as a service facility or as a collaborative venture,” explained O’Holleran, who estimates that around 100 researchers will become part of the CAIC community.

“We’re also a hub. We connect researchers who’ve built their own devices and we train PhD students in the cross-disciplinary skills needed for cutting-edge imaging.”

CAIC, Klenerman, Kaminski and others have now been awarded funding as part of the Next Generation Microscopy Initiative Programme led by the Medical Research Council to help establish Cambridge as a national centre of excellence in microscopy. Part of this funding is being used for the two new super-resolution microscopes currently being built in CAIC.

̽��ֱ��researchers hope that super-resolution microscopes will one day become the workhorse of biology, allowing ever-deeper probing of living structures. Breaking the diffraction barrier of light had seemed an insurmountable barrier until recent years. With continuing advances, biologists are beginning to look beyond imaging single cells to the possibility of moving through tissues, tracking the movement of molecules in three dimensions and visualising the process of life unfolding.

Inset image: What was once a fuzzy glow (left of image) can now be super-resolved (right) even if, as here, the structures are smaller than the wavelength of light; credit: Laurie Young, Florian Stroehl and Clemens Kaminski

Cambridge scientists are part of a resolution revolution. Building powerful instruments that shatter the physical limits of optical microscopy, they are beginning to watch molecular processes as they happen, and in three dimensions.

These exciting discoveries have emerged through years of painstaking research by physical scientists trying to better understand how light interacts with matter at a fundamental level

Steven Lee

̽��ֱ��Super-Resolution Revolution

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Offensive manoeuvres in the war against HIV

lw355 — Mon, 25 Feb 2013 10:31:53 +0000

It was in Los Angeles in 1981 that the first report emerged of an unusual cluster of patients whose immune systems appeared to have failed. This report is now acknowledged as the first scientific account of an infectious disease that was to become the HIV/AIDS global epidemic, infecting 60 million people and killing 25 million to date

Three decades later, and with more than 20 antiretroviral drugs to combat HIV, treatment can now significantly prolong life and reduce the rate of viral transmission. For some patients, life expectancy with uninterrupted treatment is now similar to that of someone who is not infected with HIV – not the death sentence it once was – and the global rate of new infections is at last declining.

Yet, current therapies do not fully restore health and, in resource-poor settings, patients often lack access to antiretroviral drugs. Moreover, because the virus has the ability to insert its genetic material into the genetic material of the patient’s cells, ‘latent’ viruses can re-emerge at any point, necessitating lifelong drug treatment.

“There is no imminent prospect of a vaccine, and there may not be one in the way that we have for measles and mumps, where our own immune system can clear the virus,” explained Andrew Lever, Professor of Infectious Diseases in the Department of Medicine and Honorary Consultant Physician at Addenbrooke’s Hospital. “ ̽��ֱ��bottom line is 60 million immune systems have had a crack at eradicating HIV and all have failed.”

̽��ֱ��virus is both adaptable and versatile, escaping drug treatment by mutating the structure of its proteins. Patients require combinations of drugs – an approach known as highly active antiretroviral therapy (HAART) – because this reduces the chance that a virus will mutate sufficiently to escape all.

Continued research efforts are therefore urgently required, as Lever explained: “ ̽��ֱ��big areas in HIV research are finding new drugs to complement the ones we’ve got already, so as to outrun the virus in terms of resistance, and finding a means to eradicate the latent virus.”

Lever’s research, which has been investigating the mechanisms of HIV infection for almost 25 years, is helping to tackle both of these challenges.

Structural traps

Anti-HIV drugs typically target viral proteins that are involved in the process of entering or exiting the cell. But, as Lever explained, this lies at the heart of resistance to the virus: “Proteins are very adaptable. Time and again the virus escapes the drug by altering its protein structure so that it still functions but the drug no longer recognises it. We decided instead to target the virus’ RNA genetic material.”

Lever’s previous studies had provided fundamental insights into the way in which RNA is packaged, a process that he realised could provide a remarkable opportunity for a completely new type of antiretroviral therapeutic.

For the virus RNA to be packaged and released from the cell as an intact virus particle, it must twist itself into a three-dimensional knot-like structure. It was this structure which Lever and colleagues discovered is used as a packaging signal by the virus. To form the structure, the sequence of the RNA must be highly conserved between viruses. As a result, opportunities for ‘escape mutation’ are limited. A virus protein called Gag uses the knot-like structure to pick out the viral RNA from the thousands of cellular RNAs that are an integral part of the process by which a cell translates the information in its DNA into molecules that enable the cell to function.

Interfering with Gag binding can potentially stop the virus spreading from cell to cell. In collaboration with Professor Shankar Balasubramanian and Dr Neil Bell in the Department of Chemistry, and researchers at the ̽��ֱ�� of Sussex, Lever is now using this phenomenon as the basis for designing novel antiviral drugs. In parallel, work with Professor David Klenerman in the Department of Chemistry is providing the first high-resolution data on the precise conformation of the RNA structure.

̽��ֱ��goal is to create a ‘structural trap’ in which small-molecule drugs lock the RNA in a conformation that can no longer interact properly with Gag. Targeting the function of RNA through its 3D structure is a new direction for antiviral drug discovery, and sufficiently challenging to receive funding from the Medical Research Council Milstein Fund – specifically intended for ‘high-risk, high-reward’ studies.

Using an assay they developed for measuring the interaction between Gag and RNA, the team is now screening a library of small drug-like molecules for those with potential to interfere with the process. “Although it’s very early stages, the molecular hypothesis that we started with for targeting this structure has taken us to a situation where we have molecules that look like they are doing something interesting in the assay,” said Balasubramanian. “Being able to target RNA in this way would be a paradigm shift in terms of new therapeutics for HIV, and other infectious diseases.”

Will RNA-directed therapeutics overcome viral resistance? “It’s a good question and untested,” added Balasubramanian. “Once we find a good small molecule that disrupts binding and packaging then we can address exactly this question.”

Curing HIV

Drug discovery is a key area for the future. However, the scientists also have their eyes on an even bigger prize – a cure for HIV – and a new collaboration between five UK Biomedical Research Centres (BRCs) is now working towards understanding how to rid the body of latent virus.

“Because latent virus exists only as genetic material, essentially indistinguishable from the genetic material of the patient’s cells, it’s effectively hidden. ̽��ֱ��patient’s immune system can’t see these infected cells and the drugs can’t target them,” explained Lever. “ ̽��ֱ��reservoir of infection sits there for years because it’s in very long-lived immune cells. Even if you suppress the virus right down using drug treatment, as soon as you stop the drugs it bounces right back with viruses that, based on their genetic sequence, are historically very old, so these have been latent for a long time.”

̽��ֱ��new project, CHERUB (Collaborative HIV Eradication of Viral Reservoirs: UK BRC), funded by the National Institute for Health Research, brings together researchers from Imperial College, King’s College Biobank, ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and ̽��ֱ�� of Oxford, and is the first pan-BRC cooperative project to compete internationally in a new field of biomedical research.

Lever leads the Cambridge contribution along with Dr Mark Wills and Dr Axel Fun from the Department of Medicine. “Until we learn how to eradicate the latent virus then all we can do is contain it,” Lever explained. “CHERUB will work in collaboration with NHS Trusts and the pharmaceutical industry to recruit new patient cohorts for studies that range from fundamental laboratory research through to large-scale clinical trials of novel agents.”

̽��ֱ��Cambridge researchers will develop an assay to detect latent virus that will be used to provide a measure of the relative success of drugs, as well as expand current research areas to learn new ways to rouse the virus from its latency.

“All HIV patients have latent virus – it’s a fact of life,” added Lever. “You can suppress active viruses with current conventional drugs so that the patient’s immune system recovers but you can’t get rid of the latent virus. ̽��ֱ��aim now is to suppress the virus to the point where the immune system recovers but at the same time to wake up and eradicate the virus from the latently infected cells. And then we are talking about a cure.”

For more information, please contact Louise Walsh at the ̽��ֱ�� of Cambridge Office of External Affairs and Communications.

Although anti-HIV drugs can significantly prolong life, patients must take the drugs for the rest of their lives. New approaches to therapeutics may hold the answer to finding a cure for HIV.

̽��ֱ��bottom line is 60 million immune systems have had a crack at eradicating HIV and all have failed.

Andrew Lever

Cynthia Goldsmith, Centers for Disease Control and Prevention

HIV-1 budding from a cultured cell

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