Every few years, a bloom of microscopic organisms called dinoflagellates transforms the coasts around the world by endowing breaking waves with an eerie blue glow. This year’s spectacular bloom in southern California was a particularly striking example. In a new study published in the journal Physical Review Letters, researchers have identified the underlying physics that results in light production in one species of these organisms.

The international team, led by the University of Cambridge, developed unique experimental tools based on micromanipulation and high-speed imaging to visualise light production on the single-cell level. They showed how a single-celled organism of the species Pyrocystis lunula produces a flash of light when its cell wall is deformed by mechanical forces. Through systematic experimentation, they found that the brightness of the flash depends both on the depth of the deformation and the rate at which it is imposed.

Known as a ‘viscoelastic’ response, this behaviour is found in many complex materials such as fluids with suspended polymers. In the case of organisms like Pyrocystis lunula, known as dinoflagellates, this mechanism is most likely related to ion channels, which are specialised proteins distributed on the cell membrane. When the membrane is stressed, these channels open up, allowing calcium to move between compartments in the cell, triggering a biochemical cascade that produces light.

“Despite decades of scientific research, primarily within the field of biochemistry, the physical mechanism by which fluid flow triggers light production has remained unclear,” said Professor Raymond E. Goldstein, the Schlumberger Professor of Complex Physical Systems in the Department of Applied Mathematics and Theoretical Physics, who led the research.

“Our findings reveal the physical mechanism by which the fluid flow triggers light production and show how elegant decision-making can be on a single-cell level,” said Dr Maziyar Jalaal, the paper’s first author.

Bioluminescence has been of interest to humankind for thousands of years, as it is visible as the glow of night-time breaking waves in the ocean or the spark of fireflies in the forest. Many authors and philosophers have written about bioluminescence, from Aristotle to Shakespeare, who in Hamlet wrote about the ‘uneffectual fire’ of the glow-worm; a reference to production of light without heat:

"…To prick and sting her. Fare thee well at once / The glowworm shows the matin to be near / And 'gins to pale his uneffectual fire. / Adieu, adieu, adieu. Remember me.”

The bioluminescence in the ocean is, however, not ‘uneffectual.’ In contrast, it is used for defence, offense, and mating. In the case of dinoflagellates, they use light production to scare off predators.

The results of the current study show that when the deformation of the cell wall is small, the light intensity is small no matter how rapidly the indentation is made, and it is also small when the indentation is large but applied slowly. Only when both the amplitude and rate are large is the light intensity maximised. The group developed a mathematical model that was able to explain these observations quantitatively, and they suggest that this behaviour can act as a filter to avoid spurious light flashes from being triggered

In the meantime, the researchers plan to analyse more quantitatively the distribution of forces over the entire cells in the fluid flow, a step towards understanding the light prediction in a marine context.

Other members of the research team were postdoctoral researcher Hélène de Maleprade, visiting students Nico Schramma from the Max-Planck Institute for Dynamics and Self-Organization in Göttingen, Germany and Antoine Dode from the Ècole Polytechnique in France, and visiting professor Christophe Raufaste from the Institut de Physique de Nice, France.

The work was supported by the Marine Microbiology Initiative of the Gordon and Betty Moore Foundation, the Schlumberger Chair Fund, the French National Research Agency, and the Wellcome Trust.

Reference:
M. Jalaal, N. Schramma, A. Dode, H. de Maleprade, C. Raufaste, and R.E. Goldstein. ‘Stress-Induced Dinoflagellate Bioluminescence at the Single Cell Level.’ Physical Review Letters (2020). DOI: 10.1103/PhysRevLett.125.028102

The researchers, from the University of Cambridge, Cornell University and Stanford University, say their device could mimic any cell type--bacterial, human or even the tough cells walls of plants. Their research recently pivoted to how COVID-19 attacks human cell membranes and, more importantly, how it can be blocked.

The devices have been formed on chips while preserving the orientation and functionality of the cell membrane and have been successfully used to monitor the activity of ion channels, a class of protein in human cells which are the target of more than 60% of approved pharmaceuticals. The results are published in two recent papers in Langmuir and ACS Nano.

Cell membranes play a central role in biological signalling, controlling everything from pain relief to infection by a virus, acting as the gatekeeper between a cell and the outside world. The team set out to create a sensor that preserves all of the critical aspects of a cell membrane—structure, fluidity, and control over ion movement—without the time-consuming steps needed to keep a cell alive.

The device uses an electronic chip to measure any changes in an overlying membrane extracted from a cell, enabling the scientists to safely and easily understand how the cell interacts with the outside world.

The device integrates cell membranes with conducting polymer electrodes and transistors. To generate the on-chip membranes, the Cornell team first optimised a process to produce membranes from live cells and then, working with the Cambridge team, coaxed them onto polymeric electrodes in a way that preserved all of their functionality. The hydrated conducting polymers provide a more ‘natural’ environment for cell membranes and allows robust monitoring of membrane function.

The Stanford team optimised the polymeric electrodes for monitoring changes in the membranes. The device no longer relies on live cells that are often technically challenging to keep alive and require significant attention, and measurements can last over an extended time period.

“Because the membranes are produced from human cells, it’s like having a biopsy of that cell’s surface - we have all the material that would be present including proteins and lipids, but none of the challenges of using live cells,” said Dr Susan Daniel, associate professor of chemical and biomolecular engineering at Cornell and senior author of the ACSLangmuir paper.

“This type of screening is typically done by the pharmaceutical industry with live cells, but our device provides an easier alternative,” said Dr Róisín Owens from Cambridge’s Department of Chemical Engineering and Biotechnology, and senior author of the ACS Nano paper. “This method is compatible with high-throughput screening and would reduce the number of false positives making it through into the R&D pipeline.”

“The device can be as small as the size of a human cell and easily fabricated in arrays, which allows us to perform multiple measurements at the same time,” said Dr Anna-Maria Pappa, also from Cambridge and joint first author on both papers.

To date, the aim of the research, supported by funding from the United States Defense Research Projects Agency (DARPA), has been to demonstrate how viruses such as influenza interact with cells. Now, DARPA has provided additional funding to test the device’s effectiveness in screening for potential drug candidates for COVID-19 in a safe and effective way.

Given the significant risks involved to researchers working on SARS-CoV-2, the virus which causes COVID-19, scientists on the project will focus on making virus membranes and fusing those with the chips. The virus membranes are identical to the SARS-CoV-2 membrane but don’t contain the viral nucleic acid. This way new drugs or antibodies to neutralise the virus spikes that are used to gain entry into the host cell can be identified. This work is expected to get underway on 1 August.

“With this device, we are not exposed to risky working environments for combating SARS-CoV-2. The device will speed up the screening of drug candidates and provide answers to questions about how this virus works,” said Dr Han-Yuan Liu, Cornell researcher and joint first author on both papers.

Future work will focus on scaling up production of the devices at Stanford and automating the integration of the membranes with the chips, leveraging the fluidics expertise from Stanford PI Juan Santiago who will join the team in August.

“This project has merged ideas and concepts from laboratories in the UK, California and New York, and shown a device that works reproducibly in all three sites. It is a great example of the power of integrating biology and materials science in addressing global problems,” said Stanford lead PI Professor Alberto Salleo.

References:
H-Y Liu et al. “Self-assembly of mammalian cell membranes on bioelectronic devices with functional transmembrane proteins.” ACS Langmuir (2020). DOI: 10.1021/acs.langmuir.0c00804

A-M. Pappa et al.“Optical and Electronic Ion Channel Monitoring from Native Human Membranes.” ACS Nano (2020). DOI: 10.1021/acsnano.0c01330

Lack of physical activity and exercise are known risk factors for major health conditions, including cognitive impairments such as memory and concentration problems. However, evidence as to whether physical activity actually protects against cognitive decline has often been mixed and inconclusive.

Researchers at the University of Cambridge examined patterns of physical activity among 8,500 men and women who were aged 40-79 years old at the start of the study and who had a wide range of socioeconomic backgrounds and educational attainment. The individuals were all part of the EPIC-Norfolk Cohort. In particular, the team were able to separate physical activity during work and leisure to see if these had different associations with later life cognition.

“The often used mantra ‘what is good for the heart, is good for the brain’ makes complete sense, but the evidence on what we need to do as individuals can be confusing,” said Shabina Hayat from the Department of Public Health and Primary Care at the University of Cambridge. “With our large cohort of volunteers, we were able to explore the relationship between different types of physical activity in a variety of settings.”

As part of the study, participants completed a health and lifestyle questionnaire, including information on the level of physical activity during both work and leisure, and underwent a health examination. After an average 12 years, the volunteers were invited back and completed a battery of tests that measured aspects of their cognition, including memory, attention, visual processing speed and a reading ability test that approximates IQ.

While many studies have only been able to report cross-sectional findings, the ability to follow up EPIC-Norfolk participants over a long period allowed the researchers to examine data prospectively. This helped them rule out any bias resulting from people with poor cognition – possibly as a result of cognitive impairment or early dementia – being less likely to be physically active due to poor cognition, rather than poor cognition being a result of physical inactivity.

Among their findings, published today in the International Journal of Epidemiology, the researchers report:

• Individuals with no qualifications were more likely to have physically active jobs, but less likely to be physically active outside of work.
• A physically inactive job (typically a desk-job), is associated with lower risk of poor cognition, irrespective of the level of education.  Those who remained in this type of work throughout the study period were the most likely to be in the top 10% of performers.
• Those in manual work had almost three times increased risk of poor cognition than those with an inactive job.

“Our analysis shows that the relationship between physical activity and cognitive is not straightforward,” explained Hayat. “While regular physical activity has considerable benefits for protection against many chronic diseases, other factors may influence its effect on future poor cognition.

“People who have less active jobs – typically office-based, desk jobs – performed better at cognitive tests regardless of their education. This suggests that because desk jobs tend to be more mentally challenging than manual occupations, they may offer protection against cognitive decline.”

It was not possible to say conclusively that physical activity in leisure time and desk-based work offer protection against cognitive decline. The researchers say that to answer this question, further studies will be required to include a more detailed exploration of the relationship of physical activity with cognition, particularly on inequalities across socio-economic groups and the impact of lower education.

The research was supported by the Medical Research Council, Cancer Research UK and the National Institute for Health Research.

Reference
Hayat, SA et al. Cross-sectional and prospective relationship between occupational and leisure time inactivity and cognitive function in an ageing population. The European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk) Study. International Journal of Epidemiology; 7 Jul 2020; DOI: 10.17863/CAM.51130

EMBO Membership honours distinguished scientists who have made outstanding contributions to the life sciences, including 88 Nobel Laureates. It is an international organisation of life scientists, which has more than 1800 members elected by peers.

The newly elected Cambridge researchers are:

Professor Bertie Göttgens, Professor of Molecular Haematology, Deputy Director of the Wellcome MRC Stem Cell Institute, and a member of the Cancer Research UK (CRUK) Cambridge Centre Haematological Malignancies Programme. Bertie’s research group studies how transcription factor networks control the function of blood stem cells, and how mutations that perturb these networks cause leukaemia.

Göttgens said:"This honour is very much a reflection of the dedicated work and collective effort of all members of my research group over the years. Rather fittingly, I kick-started my independent career with a paper in an EMBO Journal. Becoming an EMBO member therefore represents a very special milestone to me."

Professor Kathryn Lilley, Director of the Cambridge Centre for Proteomics, Department of Biochemistry, Milner Therapeutics Institute, and a member of the CRUK Cambridge Centre Cell and Molecular Biology Programme. Kathryn’s research aims to interrogate how the functional proteome correlates with complexity. 

Lilley said: “I feel extremely honoured to have been elected as a member of EMBO by my peers, which also recognizes the efforts and achievements on my fabulous research group members and numerous collaborators both past and present.”

Dr Serena Nik-Zainal, a CRUK Advanced Clinician Scientist at the University’s MRC Cancer Unit, and Honorary Consultant in Clinical Genetics at Addenbrooke’s Hospital. Serena’s research combines computational and experimental approaches to understand cellular changes and mutational processes that lead to cancer and age-related disorders.

Nik-Zainal said:“It’s a great honour to become a member of EMBO, opening up opportunities for exploring new interactions with colleagues through Europe and around the world.”

Professor Giles Oldroyd FRS, Russell R Geiger Professor of Crop Science at the Sainsbury Laboratory and Director of the Crop Science Centre. Giles is leading an international programme of research that attempts to achieve more equitable and sustainable agriculture through the enhanced use of beneficial microbial associations.  

Oldroyd said: “I have long admired the work that EMBO does to strengthen and coordinate science across Europe and it is an honour to now be a part of this prestigious European fellowship of biologists.”

Professor Uta Paszkowski, Professor of Plant Molecular Genetics at the Department of Plant Sciences. Uta leads the Cereal Symbiosis Group, which investigates the molecular mechanisms underlying formation and functioning of arbuscular mycorrhizal symbioses (beneficial interactions between roots of land plants and soil fungi) in rice and maize.

Paszkowski said:“Across the organisations supporting the Life Sciences, EMBO stands out by its varied activities to advance science through facilitating knowledge exchange and career development. I am immensely honoured to be elected as a member.”

Professor Anna Philpott, Head of the School of Biological Sciences, Professor of Cancer and Developmental Biology, and member of the CRUK Cambridge Centre Paediatric Cancer Programme. Anna’s research group at the Wellcome-MRC Cambridge Stem Cell Institute studies the balance between proliferation and differentiation during development and cancer, using a range of models.  

Philpott said: “I am delighted to be invited to join an organisation that has done so much for European science.”

Dr Chris Tate, research leader at the MRC Laboratory of Molecular Biology. The research in Chris’ lab focusses on understanding the structure and function of the major cell-surface receptors in humans that are targeted by 34% of marketed small molecule drugs. 

Tate said: “The election to EMBO Membership is a great honour and will enhance my interactions with the superb scientists throughout Europe. The strength of the scientific community in Europe is amazing and we all benefit enormously from being a member of this family.”

Dr Marta Zlatic, research leader at the MRC Laboratory of Molecular Biology. Marta’s lab combines connectomics with physiology and behavioural analysis, in the tractable Drosophila larval model system, to discover the fundamental principles by which brains generate behaviour. 

Zlatic said:"I feel extremely honoured and grateful that our research is being recognized in this way."

EMBO Members can actively participate in EMBO’s initiatives by serving on the organisation's Council, committees and editorial boards, participating in the evaluation of applications for EMBO funding, acting as mentors to young scientists in the EMBO community, and advising on key activities. EMBO’s administrative headquarters are in Heidelberg, Germany. 

I’m a clinical academic working in the Department of Medicine at the University of Cambridge and at Cambridge University Hospitals NHS Foundation Trust. With most of my research team I have continued to work at Addenbrooke’s during lockdown, but we’ve all worked much longer hours than usual. In fact, until recently I hadn’t had a day off for six weeks.  

My clinical experience and research interests are in infectious diseases, microbiology and genomics. I have been involved in clinical trials of infectious diseases - including TB, HIV, viral hepatitis, Staphylococcus aureus and multidrug-resistant bacteria - in the UK and in Southeast Asia for nearly 20 years. Since moving to Cambridge my research has focussed on using genome sequencing to investigate transmission of pathogens in hospital and community settings. These skills have prepared me to respond to the COVID-19 pandemic response efforts in Cambridge.

As a clinician I’m interested in understanding the epidemiology of infectious diseases and how best to treat them. I have used my clinical trials experience to contribute to the RECOVERY trial, a randomised controlled trial of various treatments for COVID-19, as a study doctor. To date this is the world’s biggest trial of drugs to treat COVID-19 patients, and the results are regularly reviewed so that any effective treatment can be quickly made available to patients. A preliminary analysis has found that dexamethasone (a steroid drug), a cheap and readily available treatment, reduces mortality in patients with COVID-19 requiring respiratory support. 

I also set up and led a novel coronavirus vaccine trial, the ‘COV002’ trial, in Cambridge. This is a phase 2/3 trial of the vaccine developed by the University of Oxford, which is being tested in over 10,000 healthy volunteers in 19 UK centres. We rapidly assembled a team of over 70 research staff in three NHS Trusts (Cambridge University Hospitals, Royal Papworth Hospital and Cambridgeshire and Peterborough NHS Foundation Trust) in Cambridgeshire. We screened over 500 healthcare workers and vaccinated over 300 of them in just over three weeks. The results of this trial will also give us vital information on the safety and efficacy of this vaccine, production of which is already being scaled up by AstraZeneca.

I used rapid sequencing of SARS-CoV-2 virus to investigate patients with COVID-19 infections at Addenbrooke’s Hospital. This work was done in collaboration with the Department of Pathology and the Public Health England Clinical Microbiology and Public Health Laboratory, as part of the COVID-19 Genomics Consortium UK. We set up and implemented a system to rapidly sequence clinical samples and to investigate healthcare-associated COVID-19 infections by analysing epidemiological and genomic data. This information was fed back to the hospital infection control and hospital management teams to investigate suspected outbreaks and improve infection control. The data we gather will help to guide UK public health interventions and policies.
 
The biggest challenges we face relating to this pandemic are to prevent people from becoming infected with SARS-CoV-2, and to find treatments that can prevent the development of severe COVID-19 disease and save lives. Developing an effective vaccine really is key to controlling the pandemic.
 
COVID-19 is a global public health emergency that requires national and international collaborative efforts. I feel very fortunate to have been able work with outstanding clinical and academic colleagues in three NHS Trusts in Cambridgeshire, different clinical and University departments, and other UK institutions to contribute to these efforts. 

With a dedicated and enthusiastic team it’s possible to achieve extraordinary things in a short period of time. It is important to recognise what is clinically and scientifically important, and to focus all your efforts on this. 

I was due to get married in June. When the pandemic is over, I’m looking forward to seeing my friends and family, getting back to triathlon training, and getting married!

Estée Török is Clinician Scientist Fellow and a Senior Research Associate in the Department of Medicine at the University of Cambridge, and an Honorary Consultant in Infectious Diseases and Microbiology at Addenbrooke’s Hospital.

How you can support Cambridge’s COVID-19 research

Photovoltaics, or solar cells, work by absorbing sunlight to produce clean electricity. But photovoltaics can absorb only a fraction of the solar spectrum, which limits their efficiencies. The typical efficiency of a solar panel is only 18-20%.

Researchers have been searching for a way to overcome this efficiency limit with an approach that is cost-effective and can be used across the world. Recently, researchers have started developing ‘tandem’ solar cells by stacking two solar cells, absorbing complementary parts of the solar spectrum, on top of each other. The most promising of these tandem solar cells is a perovskite device stacked on a silicon device.

Almost all commercial solar cells are made from silicon, but halide perovskites are a new type of material that have quickly achieved efficiencies comparable to silicon. Perovskites absorb visible light, whereas silicon absorbs near-infrared light: a perovskite-silicon tandem solar cell could realistically achieve 35% efficiency within the next decade.

However, the challenge with these tandem solar cells is that the electrode covering the perovskite solar cell needs to be transparent, and this transparent electrode is deposited using high-energy processes that damage the perovskite.

A team of researchers from Cambridge’s Department of Materials Science and Metallurgy led by Professor Judith Driscoll and Dr Robert Hoye, working with Imperial College London and the Solar Energy Research Institute of Singapore, have developed a method to ‘print’ a protective coating of copper oxide over the perovskite device. They have shown that only a 3-nanometre thick coating is sufficient to prevent any damage to the perovskite after depositing the transparent top electrode. These devices reach 24.4% efficiency in tandem with a silicon cell. Their results are reported in the journal ACS Energy Letters.

Key to success is the ability of their oxide growth method to replicate the quality of precise, vacuum-based techniques, but in open air and much faster. This minimises any damage to the perovskite when coating it with the oxide, while ensuring that the oxide grown has high density, such than only a very thin layer is needed to completely protect the perovskite. This vapour-based ‘oxide printer’ has the potential to be scaled up to commercial standards.

Reference:
Robert A. Jagt et al. ‘Rapid Vapor-Phase Deposition of High-Mobility p-Type Buffer Layers on Perovskite Photovoltaics for Efficient Semitransparent Devices.’ ACS Energy Letters (2020). DOI: 10.1021/acsenergylett.0c00763

The team also say that strategies need to be based on local epidemic growth rate at the time, social and economic costs, existing health systems capabilities and detailed plans to implement and sustain the strategy.

The COVID-19 pandemic has been responsible for over half a million deaths globally. Many LMICs responded to the pandemic by introducing a number of measures from physical distancing to strict social distancing.

These measures have proved relatively successful in containing the disease and limiting the number of deaths in places where the risk of transmission is high, public health systems and usage are suboptimal and awareness of disease prevention practices is low. However, they have often come with tremendous negative social, economic and psychological effects.

To prevent further negative impacts of lockdown, many countries are now looking to ‘reopen’, risking population health, especially given shortcomings in surveillance infrastructure and poor diagnostic capabilities.   

In a paper published in the European Journal of Epidemiology, a team of epidemiologists from the University of Cambridge, the University of Bern, BRAC University and the National Heart Foundation in Bangladesh, have examined three community-based exit strategies, and recommend their scopes, limitations and the appropriate application in the LMICs.

Dr Rajiv Chowdhury from the University of Cambridge, lead author of the paper, said: “Successfully re-opening a country requires consideration of both the economic and social costs. Governments should approach these options with a mind-set that health and economy both are equally important to protect – reviving the economy should not take priority over preserving people’s health.”

The three approaches considered are:

Sustained mitigation

Sustained ‘mitigation-only’ approaches such as those adopted in the United Kingdom, Switzerland and other European countries, involve basic prevention measures such as mask wearing, physical distancing and the isolation of positive cases after testing.

However, the researchers point out that the relative success and ease of implementation of these approaches in high-income settings was aided by a number of factors. For example, high-income countries have the capacity to implement mass testing, population surveillance and case isolation to contain the epidemic, in addition to a high number of trained contact tracers operating in a relatively small and sparse population and high levels of adherence to the measures, including home quarantine and hygiene advice.

By contrast, in LMICs, a sustained mitigation-only approach may be unfeasible due to poor or absent nationwide population surveillance, contact tracing, testing infrastructure and critical care. For example, LMICs generally have limited supply of ventilators (around 48,000 for India’s 1.3 billion people), personal protective equipment, trained healthcare personnel and safe working conditions, compromising the healthcare system’s effectiveness.

Zonal lockdowns

Zonal lockdowns involve identifying and ‘cordoning off’ new outbreak clusters with a high number of cases, keeping contact between zones low and containing the disease within a small geographic area.

However, the authors point out that any successful implementation of zonal lockdown requires regular data feedback operations in real time to identify hotspots, including information on newly confirmed cases, updated region-specific reproduction and growth rates, and deaths by age. This may be especially difficult to introduce in LMICs due to the absence of widespread population surveillance on random selections of the population and poor reporting and testing capabilities – for example, Pakistan conducts only 0.09 tests daily per 1,000 individuals compared to 0.52 in France.

Additionally, control of transmission within zones may be an enormous undertaking. In India, where this approach has been employed, the infection size within a cordoned zone can be as high as 100-200 times that outside the zone.

Countries seeking to introduce such measures should establish within the lockdown zone public health measures, including house-to-house surveillance and case-referral systems, and emergency services. They should also create buffer zones to reduce the rates of transmission from outside the zone. Such measures may only be effective when overall population transmission is relatively low and reducing.

Rolling lockdowns

Intermittent rolling lockdowns are now advocated by the World Health Organization in various LMICs. These involve implementing strict social distancing for a set number of days before a period of relaxation. Rolling lockdowns may be particularly useful in LMICs with dense populations, where this is a high potential for contact, weak health systems and poor contact tracing.

A modelling study published by the team in May showed that a system involving 50 days of strict lockdown followed by 30 days of relaxation, enabling the economy to ‘breathe’ and recuperate, could reduce the reproduction number to 0.5, reduce the strain on health systems and considerably reduce the number of deaths compared to a situation with no lockdown.

Professor Oscar Franco, of the University of Bern and senior author of the paper, said: “Rolling lockdowns need be flexible and tailored to the specific country. The frequency and duration of the lockdowns or relaxed periods should be determined by the country based on local circumstances. They don’t necessarily need to be nationwide – they can also involve a large zone or province with very high incidence of COVID-19.”

Dr Shammi Luhar of the University of Cambridge and co-author of the paper, added: “These three strategies should not be considered as one or the other. A country should further adapt and could combine them as needed.”

Reference
Chowdhury, R et al. Long-term strategies to control COVID-19 in low and middle-income countries: an options overview of non-pharmacological interventions; 13 July 2020 

Our brains are often likened to computers, with learned skills and memories stored in the activity patterns of billions of nerve cells. However, new research shows that memories of specific events and experiences may never settle down. Instead, the activity patterns that store information can continually change, even when we are not learning anything new.

Why does this not cause the brain to forget what it has learned? The study, from the University of Cambridge, Harvard Medical School and Stanford University, reveals how the brain can reliably access stored information despite drastic changes in the brain signals that represent it.

The research, led by Dr Timothy O’Leary from Cambridge’s Department of Engineering, shows that different parts of our brain may need to relearn and keep track of information in other parts of the brain as it moves around. Their study, published in the open-access journal eLife, provides some of the first evidence that constant changes in neural activity are compatible with long term memories of learned skills.

The researchers came to this conclusion through modelling and analysis of data taken from an experiment in which mice were trained to associate a visual cue at the start of a 4.5-metre-long virtual reality maze with turning left or right at a T-junction, before navigating to a reward. The results of the 2017 study showed that single nerve cells in the brain continually changed the information they encoded about this learned task, even though the behaviour of the mice remained stable over time.

The experimental data consisted of activity patterns from hundreds of nerve cells recorded simultaneously in a part of the brain that controls and plans movement, recorded at a resolution that is not yet possible in humans.

“Finding coherent patterns in this large assembly of cells is challenging, much like trying to determine the behaviour of a swarm of insects by watching a random sample of individuals,” said O’Leary. “However, in some respects the brain itself needs to solve a similar task, because other brain areas need to extract and process information from this same population.”

Nerve cells connect to hundreds or even thousands of their neighbours and extract information by weighting and pooling it. This has a direct analogy with the methods used by pollsters in the run-up to an election: survey results from multiple sources are collected and ‘weighted’ according to their consistency. In this way, a steady pattern can emerge even when individual measurements vary wildly.

The Cambridge group used this principle to construct a decoding algorithm that extracted consistent, hidden patterns within the complex activity of hundreds of cells. They found two things. First, that there was indeed a consistent hidden pattern that could accurately predict the animal’s behaviour. Second, this consistent pattern itself gradually changes over time, but not so drastically that the decoding algorithm couldn’t keep up. This suggests that the brain continually modifies the internal code that relays information between different internal circuits.

Science fiction explores the possibility of transferring our memories and experiences into hardware devices directly from our brains. If future technology eventually allows us to upload and download our thoughts and memories, we may find that our brain cannot interpret its own activity patterns if they are replayed many years later. The concept of an apple - its colour, flavour, taste and the memories associated with it - may remain consistent, but the patterns of activity it evokes in the brain may change completely over time.

Such conundrums will likely remain speculative for the immediate future, but experimental technology that achieves a limited version of such mind reading is already a reality, as this study shows. Brain-machine interfaces are a rapidly maturing technology, and human neural interfaces that can control prosthetics and external hardware have been in clinical use for over a decade. The work from the Cambridge group highlights a major open challenge in extracting reliable information from the brain.

“Even though we can now monitor brain activity and relate it directly to memories and experiences, the activity patterns themselves continually change over a period of several days,” said O’Leary, who is a Lecturer in Information Engineering and Medical Neuroscience. “Our study shows that in spite of this change, we can construct and maintain a relatively stable ‘dictionary’ to read out what an animal is thinking as it navigates a familiar environment.

“The work suggests that our brains are never at rest, even when we are not learning anything about the external world. This has major implications for our understanding of the brain and for brain-machine interfaces and neural prosthetics.”

References:
Michael E. Rule et al. ‘Stable task information from an unstable neural population’. eLife (2020). DOI: 10.7554/eLife.51121

Depression is often thought to be a risk factor for dementia but this may be because some depression scales used by clinicians and researchers partially assess apathy, say scientists from the universities of Cambridge, King’s College London, Radboud and Oxford.

The study, published in the Journal of Neurology, Neurosurgery & Psychiatry is the first to examine the relationships between apathy, depression, and dementia in individuals with cerebral small vessel disease (SVD). SVD may occur in one out of three elderly individuals, causes about a quarter of all strokes, and is the most common cause of vascular dementia.

The team studied two independent cohorts of SVD patients, one from the UK and the other from the Netherlands. Across both cohorts, they found that individuals with higher baseline apathy, as well as those with increasing apathy over time, had a greater risk of dementia. In contrast, neither baseline depression nor change in depression had any detectable influence on dementia risk.

These findings were consistent despite variation in the severity of participants’ symptoms, suggesting that they could be generalised across a broad spectrum of SVD cases. The relationship between apathy and dementia remained after controlling for other well-established risk factors for dementia including age, education, and cognition.

Lead author, Jonathan Tay, from Cambridge’s Department of Clinical Neurosciences said: “There has been a lot of conflicting research on the association between late-life depression and dementia. Our study suggests that may partially be due to common clinical depression scales not distinguishing between depression and apathy.”

Apathy, defined as a reduction in ‘goal-directed behaviour’, is a common neuropsychiatric symptom in SVD, and is distinct from depression, which is another symptom in SVD. Although there is some symptomatic overlap between the two, previous MRI research linked apathy, but not depression, with white matter network damage in SVD.

Jonathan Tay said: “Continued monitoring of apathy may be used to assess changes in dementia risk and inform diagnosis. Individuals identified as having high apathy, or increasing apathy over time, could be sent for more detailed clinical examinations, or be recommended for treatment.”

Over 450 participants – all with MRI-confirmed SVD – recruited from three hospitals in South London and Radboud University’s Neurology Department in the Netherlands, were assessed for apathy, depression and dementia over several years.

In the UK cohort, nearly 20% of participants developed dementia, while 11% in the Netherlands cohort did, likely due to the more severe burden of SVD in the UK cohort. In both datasets, patients who later developed dementia showed higher apathy, but similar levels of depression at baseline, compared to patients who did not.

The study provides the basis for further research, including the mechanisms that link apathy, vascular cognitive impairment, and dementia. Recent MRI work suggests that similar white matter networks underlie motivation and cognitive function in SVD. Cerebrovascular disease, which can be caused by hypertension and diabetes, can lead to network damage, resulting in an early form of dementia, presenting with apathy and cognitive deficits. Over time, SVD-related pathology increases, which is paralleled by increasing cognitive and motivational impairment, eventually becoming severe enough to meet criteria for a dementia state.

Jonathan Tay says: “This implies that apathy is not a risk factor for dementia per se, but rather an early symptom of white matter network damage. Understanding these relationships better could have major implications for the diagnosis and treatment of patients in the future.”

This work was funded by a Priority Programme Grant from the Stroke Association (2015-02) and National Institute of Health Research (NIHR) Biomedical Research Centre Dementia and Neurodegeneration Theme (146281). Jonathan Tay is supported by a Cambridge International Scholarship from the Cambridge Trust.

Reference:

J. Tay et al., ‘Apathy, but not depression, predicts all-cause dementia in cerebral small vessel disease’, Journal of Neurology, Neurosurgery & Psychiatry (July 2020). DOI: 10.1136/jnnp-2020-323092

Since the start of the UK pandemic, when the virus was spreading between people, a team of scientists and clinicians at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust (CUH) have been reading the genetic code of the virus to see if cases within the hospital are connected. This has enabled the hospital to fully investigate these outbreaks and to improve infection control measures to reduce the risk of further infections.

In addition, the introduction of a screening programme that involved repeat testing of staff, has  helped the hospital to investigate clusters of COVID-19 infections, informing infection control measures and breaking chains of transmission. This has helped reduce the number of hospital-acquired infections, ensuring maximum safety for patients and staff as the NHS aims to re-start other services.

Researchers have published details of these investigations in two peer-reviewed journals, Lancet Infectious Diseases and eLife.

Genomic surveillance

Researchers in Cambridge have previously pioneered the use of genome sequencing as a way of managing hospital infections such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and Clostridium difficile. They have also used real-time sequencing to rapidly identify transmission chains in epidemics such as the Ebola epidemic in Sierra Leone.

The researchers have now turned their attention to COVID-19.

SARS-CoV-2, the coronavirus that causes COVID-19, is an RNA virus and as such its genetic code is prone to errors each time it replicates. It is currently estimated that the virus mutates at a rate of 2.5 nucleotides (the A, C, G and T of genetic code) per month. Reading – or ‘sequencing’ – the genetic code of the virus can provide valuable information on its biology and transmission.

As part of the COVID-19 Genomics UK (COG-UK) Consortium, researchers have been sequencing all available positive samples from patients admitted to the hospital with COVID-19 infection as well as a selection of samples collected from patients in regional hospitals across the East of England.

In a five week period from mid-March to late April, the team sequenced over 1,000 viral genomes. They used phylogenetic trees – akin to a ‘family tree’ – to look at how clusters of virus samples might be related, allowing them to help pinpoint particular wards or locations where the disease was spreading.

Dr Estée Török from the Department of Medicine at the University of Cambridge said: “Genome sequencing gives us a rapid and reliable way of identifying cases of COVID-19 infection that are closely related within the hospital. This approach can provide vital information to help us to investigate the possible routes of transmission and to improve infection control measures to limit the spread of infection.”

The researchers analysed 299 COVID-19 patients and found 35 clusters of genetically identical viruses involving 159 patients. By examining the patients’ medical records and ward location data researchers identified strong links between 58% of cases and plausible links between 20% of cases. The epidemiological and genomic data were fed back to the hospital infection control and management teams resulting in implementation of a range of measures to prevent further transmission, including isolation of infected patients, revised procedures for ward cleaning, enhanced use of personal protective equipment (PPE) and changes in staff social distancing behaviour.

As an example, six dialysis patients were admitted to different locations in the hospital with COVID-19 infection over a three-week period. Sequencing revealed that their viral genomes were identical. Epidemiological investigation showed that the patients dialysed at the same outpatient dialysis unit on the same days of the week and identified shared patient transportation and neighbouring dialysis chairs as risk factors for transmission. This enabled the infection control team to enhance infection control measures and prevented additional cases.

Professor Ian Goodfellow, from the Department of Pathology at the University of Cambridge, said: “We’re able to combine genomic data with patients’ medical records to provide real time information to help the hospital review its infection control on a weekly basis. It’s also highlighted possible transmission networks less well documented, such as care homes, outpatient units and ambulance services.”

The COVID-19 Genomics UK Consortium is supported by funding from the Medical Research Council, part of UK Research & Innovation (UKRI), the National Institute of Health Research and the Wellcome Sanger Institute.

Screening asymptomatic and symptomatic healthcare workers

In addition to genomic surveillance, CUH has implemented a screening programme in which all staff – both symptomatic and asymptomatic – are screened.

In May, Cambridge researchers reported that of the more than 1,000 staff members reporting fit for duty during April, 3% tested positive for the coronavirus.

Now, in a follow-up study published in eLife, they have found that, alongside a decline in patient admissions with COVID-19, the proportion of both asymptomatic and symptomatic healthcare workers testing positive declined rapidly throughout the following month.

The team performed 3,388 tests at CUH between 25 April and 24 May. These included 2,611 tests on asymptomatic healthcare workers. The samples were analysed using a technique called PCR to detect genetic information from the virus on the swab.

The researchers found that just 21 (0.8%) of the 2,611 tests carried out on asymptomatic healthcare workers returned positive, a large drop compared to the previous month.

Of the 771 tests carried out on symptomatic healthcare workers or those living with someone with possible infection, just 13 (1.7%) were positive – compared to 13% the previous month.

Dr Mike Weekes, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), said: “Screening all staff at the hospital regardless of whether they are showing symptoms has helped us see a dramatic fall in the number of hospital-acquired infections. It means we’re able to spot new outbreaks faster, limiting their opportunity to spread.

“It’s important not to be complacent, though. There will inevitably be new outbreaks that occur – that is, unfortunately, the nature of a pandemic. But we hope our approach will help reassure both staff and patients that the hospital remains a safe place to give and receive care.”

In their report, the team give an example of where four symptomatic staff from the same general medical ward tested positive. In response, the team was able to carry out targeted screening of staff on the ward, allowing them to identify a cluster of infections and prevent further onward transmission.

“The existence of clusters of infection in specific areas of the hospital shows the potential for staff and patients to become infected within the hospital environment,” said Professor Steve Baker from CITIID. “If left unchecked, these clusters could lead to self-sustaining outbreaks. Frequent testing at CUH allowed us to spot these clusters quickly and stop any further transmission.”

The research was supported by Wellcome, the Addenbrooke’s Charitable Trust, the Medical Research Council, NHS Blood and Transfusion, National Institute for Health Research Cambridge Biomedical Research Centre and Cancer Research UK.

Reference

Meredith, LW, Hamilton, WL, et al. Rapid implementation of real-time SARS-CoV-2 sequencing to investigate healthcare-associated COVID-19 infections. Lancet ID; 14 July 2020; DOI: 10.1016/S1473-3099(20)30562-4

Jones, NK, Rivett, L, Sparkes, D, and Forrest, S et al. Effective control of healthcare worker SARS-CoV-2 transmission in a period of declining community prevalence of COVID-19. eLife; 19 June 2020; DOI: 0.7554/eLife.59391

I run a lab in the Jeffrey Cheah Biomedical Centre (JCBC) on the Cambridge Biomedical Campus, where we study antibiotic resistance and infections. We work closely with Cambridge University Hospitals (CUH), applying genomics to analyse clinical samples. I’m also a strategic advisor to Wellcome, and until recently was spending two days a week at its headquarters in London. I’m now spending all my working time in the JCBC, continuing to work remotely for Wellcome. I’ve worked throughout the lockdown.

My team was involved in setting up COVID-19 testing for healthcare workers, and establishing a containment level 3 facility (designed to safely handle infectious diseases) for this. It was hard work, but I believe it made a major impact on reducing COVID in the hospital and department so it has been very rewarding. The group is now slowly stepping back from testing and returning to our normal work.

I also helped establish the COVID-19 Genomics UK (COG-UK) Consortium for sequencing the virus, together with the Principal Investigator Sharon Peacock. I did a lot of the organisational work, including setting up the grant with the University. This was all done at very short notice. Ian Goodfellow is head of sequencing for Cambridge COG-UK, and has been great at linking with the hospital. We also helped out with the Intensive Care Unit at the peak of the pandemic, looking for secondary infections and antibiotic resistance.

My lab works on the molecular mechanisms involved in infection and resistance to treatments. We use simple models of infection, mostly based around high throughput genomic assays and models based on human stem cells. I also have global connections for my work on typhoid - multiple field sites around the world managed partly through joint funding with the International Vaccine Institute from Gates, EU, and Wellcome. We run projects working on maximising the amount of useful data returned on the analysis of samples, both on these sites and within the Cambridge hospital system.

I’ve been working on epidemics all my life, so in some ways I’ve just carried on as normal. I have always been very careful about things like social distancing and hand-washing when traveling in epidemic areas, so this is quite natural for me and my team. I think it’s now a psychological battle to get back to normality. In many parts of the world people still live on a daily basis with diseases like cholera, typhoid and malaria. 

The UK infrastructure was absolutely not ready for COVID-19. We need to learn to adapt and be ready for the next epidemic, because if we carry on the way we are there will be another one and it could be a lot worse, for example by affecting children - who are largely spared by COVID-19.

The research community’s response to COVID-19 could have been better. Obviously the lockdown has meant that it’s very difficult to find people to get anything done. Some people have stepped up and been excellent; others have struggled. We need to learn from this: the multiple levels of administration within organisations need to be simplified. Ironically during the pandemic we were more or less left to get on with things and I’m sure that helped us.

We need a much better local infrastructure both within hospitals and the community. For example, track and test cannot be invented during an epidemic; it has to be in place already. The clinicians, scientists and management within CUH have been fantastic in my opinion, but we need the infrastructure to match. We now have excellent facilities coming online in the JCBC but we need more. We need to re-establish health clinics in the community, and get GPs out of their offices and back out there (this is absolutely not a criticism of GPs, I am sure they would agree!). 

When the pandemic is over I’m looking forward to going on holiday and having a meal out with my wife…..and watching Scunthorpe United.
 
Gordon Dougan FRS is an expert on vaccines and genomics whose distinguished career has included contribution to the development of several vaccines. He is a Professor at the Cambridge Institute for Therapeutic Immunology & Infectious Disease (CITIID) in the Department of Medicine. He recently wrote a blog on How we lost our collective memory of epidemics.

How you can support Cambridge’s COVID-19 research

The grants, from the Research England Development (RED) Fund, will support two new programmes: TenU and a new Policy Evidence Unit for University Commercialisation and Innovation (UCI), which will be based at Cambridge’s Institute for Manufacturing (IfM).

TenU will bring together the heads of technology transfer offices (TTOs) from ten of the world’s leading universities to share expertise and experience to develop, improve, and disseminate best practice in research commercialisation. UCI will undertake research to create the evidence base for informing research commercialisation policy for government and universities. The two groups will work closely in areas of mutual interest.

Research from the TenU universities has led to world-changing innovations such as rapid whole-genome sequencing, the page rank algorithm technology that became the basis for Google, the world’s first artificial vaccine against viral hepatitis B, fibre optics, one of the most widely used medications for HIV treatment, and programmed T cell therapies.

As countries work to rebuild their economies in the wake of COVID-19, university TTOs will play a critical role in turning early-stage, research-based innovations into new products and services across different sectors. In the UK, the Industrial Strategy has identified universities as key drivers of innovation.

“We welcome this vital support from Research England, which enables us to continue to share, compare, and advance international best practice in university research commercialisation for the benefit of our economies and societies locally, nationally, and globally,” said Tony Raven, CEO of Cambridge Enterprise, the University of Cambridge’s commercialisation arm.

Apart from Cambridge, the other members of TenU are Columbia, Edinburgh, Imperial College London, Leuven, Manchester, MIT, Stanford, Oxford, and University College London.

The Policy Evidence Unit for University Commercialisation and Innovation (UCI), based at Cambridge’s Institute for Manufacturing, will help to drive a step change in universities’ contributions to delivering increased R&D and innovation in the UK.

The new unit will be developed in partnership with the Centre for Science, Technology and Innovation Policy (CSTI) and the National Centre for Universities and Business (NCUB). It will support the needs of government departments, funding agencies, and universities for better data, evidence, and expert insights, to develop more effective approaches for university commercialisation and innovation.

The needs for better evidence are growing as we move from the immediate COVID-19 crisis into the longer-term economic recovery period, and as the government looks to maximise the value realised from its investment in the research base. Universities need to find new ways of working with businesses, investors and others to open up opportunities, address emerging innovation challenges, and improve productivity. To unlock this potential, governments will have to adapt policies and funding programmes to become key enabling partners in this process.

Working closely with key stakeholders, UCI will initially focus on three areas:

• Developing an evidence base on how the COVID-19 induced economic crisis is affecting universities’ abilities to contribute to innovation and identify possible actions to ensure they are able to play a strategic and active role in the national economic recovery.
• Improving our understanding of the research-to-innovation commercialisation journeys and examine how policies and university practices could be strengthened to deliver increased value to the UK.
• Advancing the data and metrics available to better capture the performance of universities in delivering economic and social impacts through their commercialisation activities to facilitate more effective benchmarking and evaluation of performance.

Tomas Ulrichsen, Director of the new Policy Evidence Unit for University Commercialisation and Innovation, said: “I am delighted to bring expertise from CSTI, the University of Cambridge, and NCUB together to establish this important new policy evidence unit. The grant from the Research England Development Fund will enable us to support policymakers, funders, and universities with better and more targeted evidence and expert insight, to consider how to build on and adapt their approaches to university-driven commercialisation and innovation. This will help economies across the UK recover, reconfigure, and thrive through the economic recovery following the COVID-19 pandemic.”

“In line with the UK Government’s R&D Roadmap, Research England as part of UK Research and Innovation needs to demonstrate we are world class at securing economic and social benefits from research,” said David Sweeney, Executive Chair of Research England. “University technology transfer is at the heart of that. Research England funding for TenU will help showcase best practice at the global cutting edge, with the new UCI policy unit providing critical evidence and metrics. We look forward to deepening these international links.”

The finding is one of numerous results and recommendations in a new book about the language development of EAL pupils, and its impact on their attainment and social integration. The book, authored by a team of academics from Cambridge, Anglia Ruskin and Durham Universities, examines the complex relationship between language, education and the social integration of newcomer migrant EAL students.

According to the School Census, there are currently over 1.5 million EAL pupils in England, and the proportion is steadily rising. The trend is similar in many other English-speaking countries.

The book builds on three years of research involving over 40 schools across the East of England, funded by the Bell Foundation, and highlights much good practice by teachers working in multilingual classrooms. But it also points to inconsistencies and gaps in support for EAL pupils, stemming from an absence of national guidelines, targeted assessment, and systemic problems in areas such as teacher training and school-parent communication.

EAL pupils themselves were found to make uneven progress during their first two years in English schools. While many became competent English-speakers, their written English frequently lagged behind. The authors suggest this pattern may be further exacerbated by reductions in funding for EAL support.

As well as analysing the progress of EAL pupils, the study proposes a model for a more inclusive approach to teaching EAL students.

Dr Karen Forbes, Lecturer at the Faculty of Education, University of Cambridge, said: “At the moment, it is often left to individual teachers or schools to decide how to handle the challenges of a multilingual classroom. While many do excellent work, EAL pupils inevitably have a variable experience. Teachers and schools should be able to draw on a structured framework and a proper knowledge base so that they can give these pupils the sustained linguistic and educational support they often need.”

The research suggests that while many schools rightly prioritise the integration of EAL learners into mainstream lessons, some will need ongoing, one-to-one support, especially with developing more academic English, long past the point where they appear socially-integrated and able to hold a casual conversation.

This is just one symptom of a wider need to provide schools with a structural basis to give EAL learners individualised, ‘child-centred’ support, the authors argue. They stress that the ‘EAL’ label does not describe one type of pupil, but encompasses a wide range of previous educational experiences, interests and skills.

Encouragingly, many of the schools surveyed actively encouraged an inclusive and positive environment for EAL pupils. Teachers also employed various tactics that could form part of a wider framework to support them, such as group learning and buddy systems, translated texts and different visual aids.

But the study finds that many such interventions are devised locally, by schools or individual teachers, absent more structured or systematic guidance. This can lead to inconsistencies: for example, teachers varied their approach to when EAL pupils could use their home language, which often left students confused about when to use English.

The researchers argue that other mechanisms are needed to give teachers a more solid foundation for working with EAL pupils. Teachers consistently enthused, for example, about the ‘vital’ support provided by dedicated EAL co-ordinators and bilingual support staff. But many schools that the researchers surveyed have struggled to sustain such services given that funding is no longer ring-fenced for this purpose.

The book also highlights the need for more EAL-specific, specialist training for teachers, both for their professional practice and to help them work successfully with local minority-ethnic and migrant communities, especially those unfamiliar with the English system of education. This is only covered briefly in most teacher-training courses, and rarely forms part of their continuing professional development or ‘on the job’ learning.

Critically, the researchers also suggest that parents of EAL pupils and their communities are an untapped resource of knowledge, strong educational values and expertise.

The researchers found that many parents of EAL children have a high level of interest in their children’s education, but often are not sufficiently supported to understand context-specific curriculum choices, modes of assessment or school expectations. They argue that, as well as providing translated information and induction materials, schools should establish mechanisms such as EAL parents’ networks, empowering parents within school governance structures to inform the way that they support migrant pupils, ensure that they achieve their potential, and promote positive experiences in school.

“Overall, there is a need for a more systematic, whole-school approach to the education of EAL pupils,” Michael Evans, Emeritus Read in Second Language Education at the University of Cambridge, said. “This includes supporting teachers to develop their skills, providing them with a knowledge base on which to draw, and developing an effective communication system to promote parental engagement in schools. If that can be achieved, the benefits will be felt far beyond schools and EAL pupils alone.”

Language Development and Social Integration of Students with English as an Additional Language is published by Cambridge University Press on 16 July.

They show that these ten organisations carried out 1.66 million procedures, 48.7% or nearly half of the 3.40 million procedures carried out in Great Britain in 2019. More than 99% of these 1.66 million procedures were carried out on rodents or fish.

The ten organisations are listed below alongside the total number of procedures that they carried out in 2019. Each organisation’s name links to its animal research webpage, which includes more detailed statistics. This is the fifth consecutive year organisations have come together to publicise their collective numbers and examples of their research.

A further breakdown of Cambridge’s numbers, including the number of procedures by species and detail of the levels of severity, can be found on its animal research pages.

All organisations are committed to the ‘3Rs’ of replacement, reduction and refinement. This means avoiding or replacing the use of animals where possible; minimising the number of animals used per experiment and optimising the experience of the animals to improve animal welfare. However, as institutions expand and conduct more research, the total number of animals used can rise even if fewer animals are used per study.

All organisations listed are signatories to the Concordat on Openness on Animal Research in the UK, a commitment to be more open about the use of animals in scientific, medical and veterinary research in the UK. More than 120 organisations have signed the Concordat including UK universities, medical research charities, research funders, learned societies and commercial research organisations.

Wendy Jarrett, Chief Executive of Understanding Animal Research, which developed the Concordat on Openness, said: "Animal research is essential for the development of new drugs and vaccines for diseases like cancer, dementia, and COVID-19. Over the last six months we have witnessed researchers from across the world work tirelessly to develop new treatments and vaccines for COVID-19, which it is hoped can prevent thousands of further deaths. Existing drugs, developed using animals, have also been found to be effective against the virus: Remdesivir, an anti-viral drug that was initially developed using monkeys to treat Ebola, is being used to treat severe cases of COVID-19, and dexamethasone, a steroid originally developed using animal research to treat rheumatoid arthritis, has been found to save the lives of some patients on ventilators. Research involving commonly used animals like rodents, and more unusual animals like llamas, alpacas, bats, and hamsters has also yielded important information on how COVID-19 can be treated."

Over two billion people worldwide are nutrient deficient, leading to a wide range of serious health problems. Fortifying food with micronutrients is already an industry standard for enhancing public health but now scientists at Cambridge’s Department of Zoology have teamed up with Cambridge-based company BioBullets to supercharge one of the world’s most healthy and sustainable sources of animal protein: bivalve shellfish such as oysters, clams and mussels.

Dr David Aldridge and PhD student David Willer have produced the world’s first microcapsule specially designed to deliver nutrients to bivalves which are beneficial to human health. These “Vitamin Bullets” – manufactured under patent by Aldridge’s company, BioBullets – are tailored for optimal size, shape, buoyancy and to appeal to shellfish.

This breakthrough, described in a study published today in the journal Frontiers in Nutrition, is particularly valuable because when we eat bivalves, we consume the entire organism including its gut, meaning that we digest the nutrients which the animals consumed towards the end of their lives. This makes bivalve shellfish the ideal target for nutritional fortification.

In their Cambridge laboratory, the scientists trialled Vitamin A and D fortified microcapsules on over 100 oysters to identify the optimal dose. They also established that this should be fed for 8 hours towards the end of “depuration”, the period in which bivalves are held in cleansing tanks after being harvested.

The team found that fortified oysters delivered around 100 times more Vitamin A, and over 150 times more Vitamin D, than natural oysters. Even more importantly, they dramatically outperformed salmon, one of the best natural sources of these vitamins. The fortified oysters provided more than 26 times more Vitamin A and over four times more Vitamin D than salmon. The scientists found that a serving of just two of their supercharged shellfish provided enough Vitamin A and D to meet human Recommended Dietary Allowance (RDAs). 

Vitamin A and D deficiencies pose a particularly serious public health challenge – in Ghana more than 76% of children are Vitamin A deficient, causing widespread mortality and blindness. In India, 85% of the population is Vitamin D deficient, which causes cardiovascular diseases, osteoporosis, and rickets. Even in the US, over 40% of people are Vitamin D deficient.

David Willer said: “We have demonstrated a cheap and effective way to get micronutrients into a sustainable and delicious source of protein. Targeted use of this technology in regions worst affected by nutrient deficiencies, using carefully selected bivalve species and micronutrients, could help improve the health of millions, while also reducing the harm that meat production is doing to the environment”.

David Aldridge said: “We are very excited about BioBullets’ potential. We are now establishing links with some of the world’s biggest seafood manufacturers to drive a step change in the sustainability and nutritional value of the seafood that we consume.”

Bivalves have a higher protein content than beef, are a rich source of omega-3 fatty acids, and have some of the highest levels of key minerals of all animal foods. Nevertheless, the nutrients that they deliver naturally is unlikely to solve global deficiencies. These shellfish are also highly sustainable to farm, having a far lower environmental footprint than animal meat or fish, and lower even than many plant crops such as wheat, soya, and rice. 

Bivalves are a highly affordable food source when produced at large scale and the global market is rapidly expanding. Production in China alone has grown 1000-fold since 1980 and there is great potential to sustainably expand bivalve aquaculture worldwide, with over 1,500,000 km² available for sustainable low-cost industry development, particularly around the west coast of Africa and India.

The researchers point out that consumers in poorer regions where vitamin deficiencies are most prevalent are more likely to buy slightly more expensive fortified food than to make additional purchases to take supplement pills. They calculate that fortification adds just $0.0056 to the cost of producing a single oyster.

David Willer is supported by the Biotechnology and Biological Sciences Research Council; and David Aldridge is supported by The University of Cambridge, St Catharine’s College and Corpus Christi College.
 

Reference:

D.F. Willer & D.C. Aldridge, ‘Vitamin bullets. Microencapsulated feeds to fortify shellfish and tackle human nutrient deficiencies’, Frontiers in Nutrition (July 2020). DOI: 10.3389/fnut.2020.00102

The planet, the size and mass of Saturn with an orbit of thirty-five days, is among hundreds of ‘lost’ worlds that astronomers, including from the University of Cambridge, are using new techniques to track down and characterise, in the hope of finding cooler planets like those in our solar system, and even potentially habitable planets.

Reported in Astrophysical Journal Letters, the planet named NGTS-11b orbits a star 620 light-years away and is located five times closer to its sun than Earth is to our own.

The planet was originally found in a search for planets in 2018 by the University of Warwick-led team using data from NASA’s TESS telescope. This uses the transit method to spot planets, scanning for the tell-tale dip in light from the star that indicates that an object has passed between the telescope and the star.

However, TESS only scans most sections of the sky for 27 days. This means many of the longer period planets only transit once in the TESS data: without a second observation the planet is effectively lost. Researchers from Cambridge’s Cavendish Laboratory are part of the Next-Generation Transit Survey (NGTS) team which, after identifying a single transit event in the TESS data of the star NGTS-11, monitored the system in search of additional transits to confirm the planetary nature of the transiting object.

“By chasing that second transit down we’ve found a longer period planet. It’s the first of hopefully many such finds pushing to longer periods,” said lead author Dr Samuel Gill from the University of Warwick. “These discoveries are rare but important, since they allow us to find longer period planets than other astronomers are finding. Longer period planets are cooler, more like the planets in our own solar system.”

NGTS-11b has a temperature of only 160°C – cooler than Mercury or Venus. Although this is still too hot to support life as we know it, it is closer to the Goldilocks zone than many previously discovered planets which typically have temperatures above 1000°C. The Goldilocks zone refers to a range of orbits that would allow a planet or moon to support liquid water: too close to its star and it will be too hot, but too far away and it will be too cold.

“While we have discovered many planets that orbit close to their host star, we know of fewer at longer periods and cooler temperatures, which makes NGTS-11b an interesting find that takes us one step closer to finding planets in the Goldilocks zone,” said co-author Dr Ed Gillen from Cambridge’s Cavendish Laboratory. “Longer period planets like NGTS-11b may help us to better understand the various evolutionary processes that planetary systems undergo both during and after their formation.”

NGTS has twelve state-of-the-art telescopes at its site in Chile, which means that researchers can monitor multiple stars for months on end, searching for lost planets. The dip in light from NGTS-11b is only 1% deep and occurs only once every 35 days, putting it out of reach of other telescopes.

There are hundreds of single transits detected by TESS that researchers will be monitoring using this method. This will allow them to discover cooler exoplanets of all sizes, including planets more like those in our own solar system. Some of these will be small rocky planets in the Goldilocks zone that are cool enough to host liquid water oceans and potentially extra-terrestrial life.

The research was supported by the Science and Technology Facilities Council (STFC), part of UK Research and Innovation (UKRI).

Reference:
Samuel Gill et al. ‘NGTS-11 b (TOI-1847 b): A Transiting Warm Saturn Recovered from a TESS Single-transit Event.’ The Astrophysical Journal Letters (2020). DOI: 10.3847/2041-8213/ab9eb9

Adapted from a University of Warwick press release.

The findings emerged from an ongoing project which is exploring contrasts in the development of these skills in Eastern and Western societies and their relationship to academic achievement. Executive functions are cognitive skills that help us to meet goals – such as our ability to ignore distractions or switch between tasks – and they significantly affect children’s performance at school.

Across two linked studies, researchers found that the socio-economic background of British boys is directly connected to these skills. Those from wealthier families typically performed better in tests of their executive functions, while those from less-affluent backgrounds did worse.

The connection was far less direct for British girls, however – and absent altogether among boys or girls from mainland China and Hong Kong, who, despite being generally less affluent than their British peers, consistently outperformed them in the tests.

These results imply that specific cultural factors in children’s lives that shape the acquisition of executive functions, also influence socio-economic gaps in academic outcomes. It is not clear what these cultural ‘drivers’ are, but they may include differences in curriculum, parenting, or attitudes to education.

The research was by a team of academics from the Faculty of Education and the Centre for Family Research, University of Cambridge.

Dr Michelle Ellefson, Reader in Cognitive Science at the Faculty of Education, said: “Based on other research, we might have anticipated a direct link between socio-economic status and executive functions; in fact, this existed only for British boys. Pretty much any test pupils do at school requires executive functions, so if we want to reduce the achievement gap between children from different backgrounds, it’s important that we understand the mechanisms behind that relationship.”

Claire Hughes, Professor of Developmental Psychology in the Centre for Family Research, said: “There is concern in the UK that among children from less-advantaged backgrounds, boys in particular often under-perform academically, and the possibility has been raised in some research that features of their home environment play a role in this. What is interesting here is that we saw no relationship between socio-economic status and executive functions for boys in Hong Kong and China. We need to investigate why that might be the case.”

The research was part of the Family Thinking Skills project, which is exploring links between executive functions, school attainment and cultural differences in Britain and Hong Kong by comparing data from children and parents in both countries. Executive functions are mediated by the brain’s prefrontal cortex, which develops into our mid-20s, and this means that they are likely to be shaped in part by cultural influences like upbringing and environment.

The latest pair of studies looked at whether socio-economic status, which is known to influence children’s performance at school, does so because it impacts on their executive functions, or has an effect independent of cognitive skills. They also investigated how consistent the relationship is across genders. “Very little research has looked at this in Asia, and big differences with the UK might point to cultural differences driving attainment,” Ellefson said.

Initially, the researchers used data from 835 children aged 9 to 16 living in Hong Kong and the UK. The participants completed computer-based thinking games to test their executive functions, and various mathematical tests to assess numeracy. Data about socio-economic status was also provided by their parents and through a survey.

Because children in Hong Kong are highly adept with computers from an extremely young age, which might distort the results in the thinking skills tests, a second study was undertaken with 453 children in Shandong, China, led by PhD researcher Chengyi Xu. This deliberately targeted children whose use computers much less.

Overall, British students performed significantly worse in the numeracy tests, and their executive functions were about two years behind the level of their Chinese peers, even though British children tended to be from wealthier backgrounds. Within countries, there was little difference between girls’ and boys’ average test scores, although girls displayed slightly higher cognitive flexibility.

The children’s levels of executive function and socio-economic status were both shown to affect their numeracy scores, but in most cases they did so independently of each other. The exception was British boys, for whom socio-economic status directly predicts executive functions, which in turn affects their numeracy.

The researchers also measured general cognitive skills, beyond executive functions alone. Here, they found that both boys and girls from wealthier backgrounds in the UK tend to have better general cognitive skills than those from less-affluent families, whereas in China and Hong Kong, there was no relationship to socio-economic status.

The data from Shandong also confirmed that computer usage had no effect on the acquisition of executive functions.

The results strongly suggest that cultural distinctions have shaped a gulf between the thinking skills of British and Asian children, with consequences for their relative attainment. More research is needed to establish what these are, but the nature of the school curriculum, teaching styles, parental expectations, or social attitudes to education, may be some of the factors involved.

In addition, the close link between socio-economic background and thinking skills for British boys in particular suggests that understanding more about these cultural drivers may help to narrow the attainment gap within the UK. “A clearer picture of why differences exist in the development of executive functions between children in Britain and Hong Kong would potentially help to inform interventions to reduce that gap,” Hughes said.

Both studies are published in the Journal of Experimental Child Psychology.

Childbirth is widely recognised as a painful experience. However, every woman’s experience of labour and birth is unique, and the level of discomfort and pain experienced during labour varies substantially between women.

A collaboration between clinicians and scientists based at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust (CUH), and the University of Cambridge sought to investigate why some mothers report less pain during labour.

A group of women was recruited and characterised by the team led by Dr Michael Lee from the University’s Division of Anaesthesia. All the women had carried their first-born to full term and did not request any pain relief during an uncomplicated vaginal delivery. Dr Lee and colleagues carried out a number of tests on the women, including applying heat and pressure to their arms and getting them to plunge their hands into icy water.

Compared to a control group of women that experienced similar births, but were given pain relief, the test group showed higher pain thresholds for heat, cold and mechanical pressure, consistent with them not requesting pain relief during childbirth. The researchers found no differences in the emotional and cognitive abilities of either group, suggesting an intrinsic difference in their ability to detect pain.

“It is unusual for women to not request gas and air, or epidural for pain relief during labour, particularly when delivering for the first time,” said Dr Lee, joint first author. “When we tested these women, it was clear their pain threshold was generally much higher than it was for other women.” 

Next, senior co-author, Professor Geoff Woods, and his colleagues at the Cambridge Institute for Medical Research sequenced the genetic code of both groups of women and found that those in the test group had a higher-than-expected prevalence of a rare variant of the gene KCNG4. It’s estimated that one approximately 1 in 100 women carry this variant.

KCNG4 provides the code for the production of a protein that forms part of a ‘gate’, controlling the electric signal that flows along our nerve cells. As the joint first author Dr Van Lu showed, sensitivity of this gatekeeper to electric signals that had the ability to open the gate and turn nerves on was reduced by the rare variant.

This was confirmed in a study involving mice led by Dr Ewan St. John Smith from the Department of Pharmacology, who showed that the threshold at which the ‘defective’ gates open, and hence the nerve cell switches ‘on’, is higher – which may explain why women with this rare gene variant experience less pain during childbirth.

Dr St. John Smith, senior co-author, explained: “The genetic variant that we found in women who feel less pain during childbirth leads to a ‘defect’ in the formation of the switch on the nerve cells. In fact, this defect acts like a natural epidural. It means it takes a much greater signal – in other words, stronger contractions during labour – to switch it on. This makes it less likely that pain signals can reach the brain.”

“Not only have we identified a genetic variant in a new player underlying different pain sensitivities,” added senior co-author Professor Frank Reimann, “but we hope this can open avenues to the development of new drugs to manage pain.”

“This approach of studying individuals who show unexpected extremes of pain experience also may find wider application in other contexts, helping us understand how we experience pain and develop new drugs to treat it,” said Professor David Menon, senior co-author.

The research was support by the Addenbrooke’s Charitable Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome, Rosetrees Trust and the BBSRC.

Reference
Lee, M.C. et al (2020). Human labour pain is influenced by the voltage-gated potassium channel Kv6.4 subunit. Cell Reports; 21 July 2020; DOI: 10.1016/j.celrep.2020.107941

People entering Uganda have been required to quarantine for 14 days as part of the country’s lockdown measures, during which time they are monitored by the Ugandan Ministry of Health for development of COVID-19 symptoms.

Cambridge researcher Dr Rosalind Parkes-Ratanshi and her team have been helping the Ministry monitor and support quarantined individuals using a voice and SMS messaging system, Call for Life Uganda (C4LU). The tool was rapidly adapted for COVID-19 by Parkes-Ratanshi, who is based jointly at Cambridge’s Institute of Public Health and leads the Academy for Health Innovation at Infectious Diseases Institute, Makerere University, Uganda.

The C4LU system regularly phones quarantined individuals to request they report any symptoms. The automated system then generates symptom reports and anything of potential concern is flagged to healthcare professionals for triaging. This eases the burden on healthcare workers of widespread check-ups in person or by phone.

Parkes-Ratanshi and colleagues at the Infectious Diseases Institute have been using the tool for the past four years to monitor HIV patients, in collaboration with Janssen: Pharmaceutical companies of Johnson & Johnson. When the coronavirus pandemic reached Uganda, the team rapidly repurposed the system they had developed, re-scripting for COVID-19 and recording the messages in 11 of the languages spoken in Uganda.

“The total number of COVID-19 cases in Uganda has been low so far, with just over 1,000 cases across the whole country,” says Parkes-Ratanshi, who is currently based in Uganda. “Almost all cases seem to be linked to returning travellers and so the quarantine system and lockdown have been vital to slow the spread of the pandemic.”

Currently, the team are monitoring around 250 people using C4LU, with a total of 599 having participated so far. “Only a very small number of people have then needed to be tested for COVID-19, which shows the benefits of having a tool that can take pressure off the health system by reducing unnecessary visits,” she says.

Although Uganda has been fortunate in not suffering the scale of cases seen in some countries, Parkes-Ratanshi is mindful that there could be a future surge in infection. “We could see a time when regular monitoring on a wider scale would be beneficial. A system like this could reduce the number of individual calls coming in to the Ministry of Health – it could take some of the burden.”

So far, the team has focused on implementation – getting the system up and running, and triaging for possible COVID-19 cases that require confirmatory tests. They are now adding a research component, so that they can learn more about the impact of the technology, with funding from Cambridge University’s Global Challenges Research Fund QR.

The team has been asked by the Ugandan Ministry of Health to add a layer of mental health support to the tool, adds Parkes-Ratanshi. “Once you’ve gone through your symptom reporting, you might then be asked a couple of screening questions about anxiety or mental health issues. Depending on the answer, we could then offer mental health support for those people who may not need active care or active testing, but have got anxiety or mental health issues related to COVID. We think that this will also be exceedingly important to help in a situation where the health care system is very stretched.”

Crucially, the technology is appropriate to the context, says Parkes-Ratanshi: “Around 75% of people have phones in Uganda, so phone-based technology seems to be a very good way of doing this kind of public health monitoring. But it would be no good taking say a smartphone app developed in the UK and thinking it would work for Africa. Even those people who’ve got smartphones may not have access to the internet on the day they need it. So our technology is developed to work on low-cost mobile and analogue phones.”

C4LU itself is based on an open source digital system developed originally for tuberculosis patients by Janssen. “Time and resources are limited in sub-Saharan Africa. We don’t really want to be experimenting with new stuff in a pandemic, which is why we’re glad to apply our experience using this tool for HIV to COVID-19.”

Rosalind Parkes-Ratanshi is supported by several of Cambridge’s interdisciplinary networks and initiatives – Public Health, Cambridge-Africa, Infectious Diseases and Global Challenges.

How you can support Cambridge’s COVID-19 research

The University has been able to share its world-leading research expertise with the innovation and robotics know-how from its two pharmaceutical partners to create a new, high-throughput Centre at our rapidly repurposed Anne McLaren Building.

Working together at speed

Forming a collaboration between the University, AstraZeneca and GSK and the rapid creation of a state-of-the-art testing facility has been a huge undertaking and is testament not only to the strength of life science in the UK, but particularly to the work happening in the life sciences cluster in Cambridge.

The Cambridge Testing Centre is a real endeavour of partnership and ingenuity and is just one example of how organisations across the life sciences sector are working together to advance healthcare and science.

Hundreds of volunteers were recruited and trained from across the three organisations to get the Centre up and running, including researchers from the University. Each volunteer stepped forward at a time of national crisis with their own reasons for wanting to contribute to the COVID-19 testing programme.

Innovative robotics and automation were installed and an entire supply chain was sourced and implemented to ensure the testing facility was both resilient and highly effective. All of this was done in just five weeks, an operation which would usually take six months

The Centre – which soon after its launch was brought into the Government’s national diagnostic lab network – is a real example of collaboration at its best, combining the drug discovery and technology expertise of the two pharmaceutical partners with the University’s leading interdisciplinary research capabilities.

There has also been a significant contribution from a number of other British partners including Primerdesign and Bigneat, ensuring the supply of reagents and technology could meet testing needs. Teams from each of these companies stepped in to help set up the Centre, sharing expertise and mobilising people and equipment to help get the facility operational in record time.

Sir Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “We are delighted to have been able to set up both an unprecedented partnership and a state-of-the-art testing facility at speed with robotic and automation innovation at its heart. COVID-19 has posed a major challenge for the healthcare and science sectors which is why partnering with other organisations means we can continually push the boundaries of what is possible.”

Using innovation to drive delivery

Everyone at the Cambridge Testing Centre has been using their combined expertise and innovation know-how to create a highly efficient and effective laboratory. From day one, work has focused on streamlining the testing process. Combining molecular biology expertise with automation has led to a step-change in the testing process.

An innovative new COVID-19 test was also specifically designed and created for the Centre with a team from Primerdesign, part of the international diagnostics company Novacyt. The technique can be used across a number of different testing platforms to determine the presence of COVID-19 in a sample which creates a more rapid testing process.

Robots have also been installed both for RNA extraction and to automate a crucial but labour-intensive part of sample handling preparation process which improves sample integrity, ensures consistent data and reduces the man-hours required to process each sample. Before the Centre was set up, there were 13 of these robots across the UK. Now there are 14 in the Cambridge Testing Centre alone.

Three of the robots handle potentially infectious samples so are placed in individual, specialised enclosures, allowing scientists to monitor the tests without ever coming in to contact with the virus. UK company Bigneat worked double shifts and 20-hour days to design, build and install these vital new enclosures which are individually created to fit the exact requirements of where they are located, doing in a week what would normally take six.

Tony Wood, Senior Vice President, Medicinal Science & Technology, GSK said: “The innovations introduced at the Cambridge Testing Centre have been made possible by the world-class expertise of everyone involved from across the partnership. Every improvement made drives efficiency and ensures a rigorous and robust testing system is in place for now and in the future.”

Future pandemic preparedness

We wish to extend our enormous thanks to the volunteers from across the University and the pharmaceutical partners for their immense support, as many of them start to transition back to their critical roles in scientific research in the coming months.

The Centre is now transitioning to a directly employed workforce who will be trained to continue delivering this testing capability. Charles River Laboratories will manage more than 200 full-time scientists now being recruited to support the continued lab operation, which will remain at the Anne McLaren Building at the University and be overseen by AstraZeneca.

The testing innovation and improvements developed at the Cambridge Testing Centre will help form a strong foundation for a robust and sustainable diagnostics network in the UK. The impact of the work at the Centre, along with the combined efforts of the network of Lighthouse Labs, is expected to be long-lasting, contributing to the nation’s COVID-19 recovery strategy.

Chris Abell, Pro-Vice-Chancellor for Research and Professor of Biological Chemistry, University of Cambridge, said: “Our hope is that the innovation implemented at this Centre will support longer-term efforts to provide the strong foundations needed to ensure a resilient rapid diagnostics capability in the UK which is future-proof and robust.”

How you can support Cambridge's COVID-19 research effort

Donate to support COVID-19 research at Cambridge