̽��ֱ�� of Cambridge - disease

Scientists reveal plan to target the cause of Alzheimer’s disease

Anonymous — Mon, 24 Sep 2018 19:00:00 +0000

Academics at the ̽��ֱ�� of Cambridge and at Lund ̽��ֱ�� in Sweden have devised the first strategy to ‘go after’ the cause of the devastating disease, which could eventually lead to the development of new drugs to treat dementia. Their findings are reported in the journal PNAS.

“This is the first time that a systematic method to go after the pathogens – the cause of Alzheimer’s disease - has been proposed,” said Professor Michele Vendruscolo from Cambridge’s Department of Chemistry, the paper’s senior author. “Until very recently scientists couldn’t agree on what the cause was so we didn’t have a target. As the pathogens have now been identified as small clumps of proteins known as oligomers, we have been able to develop a strategy to aim drugs at these toxic particles.”

Alzheimer’s disease leads to the death of nerve cells and tissue loss throughout the brain. Over time, the brain shrinks dramatically and the cell destruction causes memory failure, personality changes, and problems carrying out daily activities.

Scientists identified abnormal deposits called protein oligomers as the most likely suspects of the cause of dementia. Although proteins are normally responsible for important cell processes, when people have Alzheimer’s disease these proteins become rogue, form clumps and kill healthy nerve cells.

“A healthy brain has a quality control system that effectively disposes of potentially dangerous masses of proteins, known as aggregates,” said Vendruscolo. “As we age, the brain becomes less able to get rid of the dangerous deposits, leading to disease. It is like a household recycling system, if you have an efficient system in place then the clutter gets disposed of in a timely manner. If not, over time, you slowly but steadily accumulate junk that you don’t need. It is the same in the brain.”

̽��ֱ��research was carried out by an international team of scientists that also included Professor Sir Christopher Dobson, Master of St John's College, ̽��ֱ�� of Cambridge, at the Centre for Misfolding Diseases (CMD), which he co-founded. “This interdisciplinary study shows that it is possible not just to find compounds that target the toxic oligomers that give rise to neurodegenerative disorders but also to increase their potency in a rational manner,” he said. “It now makes it possible to design molecules that have specific effects on the various stages of disorders such as Alzheimer’s disease, and hopefully to convert them into drugs that can be used in a clinical environment.”

There have been approximately 400 clinical trials for Alzheimer’s disease but none of them has specifically targeted the pathogens that cause it. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, cure or slow its progression.

“Our research is based on the major conceptual step of identifying protein oligomers as the pathogens and reports a method to systematically develop compounds to target them. This approach enables a new drug discovery strategy,” said Vendruscolo.

̽��ֱ��team believes their first drug candidates could reach clinical trials in around two years. They have co-founded Wren Therapeutics, a biotechnology company based in the newly opened Chemistry of Health building, whose mission is to take the ideas developed at Cambridge and translate them into finding new ways to diagnose and treat Alzheimer’s disease and other misfolding disorders.

̽��ֱ��group’s new strategy is based on a chemical kinetics approach developed in the last ten years by scientists led jointly by Professor Tuomas Knowles, also a Fellow at St John's College, Professor Dobson and Professor Vendruscolo, working at the new centre in Cambridge, in collaboration with scientists at Lund ̽��ֱ�� led by Professor Sara Linse.

“Since the process of aggregation is highly dynamic, the framework of kinetics allows us to approach this problem in a new way and find approaches to stop the generation of toxic proteins species at their very source,” said Knowles.

“This is a detailed academic study looking at how quickly compounds are able to stop amyloid building up into toxic clumps, which are characteristic of Alzheimer’s disease,” said Dr David Reynolds, Chief Scientific Officer from Alzheimer’s Research UK. “With no treatments to slow or stop the diseases that cause dementia, it’s vital we improve approaches like this that could help refine the drug discovery progress and accelerate new treatments for people living with Alzheimer’s.”

Reference:
Sean Chia et al. ‘SAR by kinetics for drug discovery in protein misfolding diseases.’ PNAS (2018). DOI: 10.1073/pnas.1807884115

Adapted from a St John’s College press release.

Researchers have developed a new way to target the toxic particles that destroy healthy brain cells in Alzheimer’s disease.

This is the first time that a systematic method to go after the pathogens – the cause of Alzheimer’s disease - has been proposed.

Michele Vendruscolo

Kateryna Kon

Conceptual image showing blurred brain with loss of neuronal networks

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Citizen science experiment predicts massive toll of flu pandemic on the UK

sc604 — Thu, 22 Mar 2018 16:03:31 +0000

̽��ֱ��numbers are frightening, but even more daunting is the very real danger of a major flu pandemic emerging at any moment. Experts around the world agree that it’s a question of when not if the next deadly pandemic will strike, making it number one on the government civilian risk register in the UK.

When it happens the pandemic will almost certainly reach the UK and the government will be faced with a series of life-saving decisions. Should we close schools or public transport? Who should be given priority when the first doses of vaccine become available? How will we cope if there is a high mortality rate? Having the right answers to these and many other crucial pandemic response questions depends on mathematical models.

̽��ֱ��model behind the results, designed by researchers at the ̽��ֱ�� of Cambridge and the London School of Hygiene and Tropical Medicine, is based on data from nearly 30,000 volunteers and represents the largest and most comprehensive dataset of its kind. ̽��ֱ��results will be broadcast on Contagion! ̽��ֱ��BBC Four Pandemic, tonight (22 March) at 9pm on BBC Four, presented by Dr Hannah Fry and Dr Javid Abdelmoneim. ̽��ֱ��results are also published in the journal Epidemics.

“ ̽��ֱ��value of predictions hinges completely on the quality of the model,” said Professor Julia Gog from Cambridge’s Department of Applied Mathematics and Theoretical Physics, who heads the disease dynamics group. “Up to now, the picture of how the population in the UK move around has been surprisingly limited, and existing studies use relatively small samples of the population. Getting a handle on how people move and interact day to day is vital to understanding how a virus will actually spread from person to person and place to place. ̽��ֱ��BBC Pandemic project has aimed to address this gap, with volunteers using an app to track movements and record who they encounter day to day, creating the biggest dataset for UK pandemic research ever collected.”

“BBC Pandemic experiment has been hugely successful in recruiting study participants,” said Dr Petra Klepac, the lead author of the paper. “ ̽��ֱ��resulting dataset is incredibly rich and will become a new gold standard in modelling contact and movement patterns that shape the spread of infectious diseases. For the programme, we were able to create a detailed UK model based on data from almost 30,000 users.”

̽��ֱ��BBC Four programme will show how a pandemic might spread in the UK, starting from Haslemere in Surrey, where the team modelled in detail an introduction starting from a hypothetical patient zero.

“We don’t know of any studies that join up the movement and survey data so comprehensively,” said Gog. “And this experiment is just huge already, an order of magnitude bigger than anything even similar. ̽��ֱ��BBC Pandemic experiment sets a new benchmark for other future studies around the world.”

̽��ֱ��study remains open during all of 2018, and anyone in the UK can volunteer by using the app (available via App Store or Google Play). Once the project is complete, the anonymised dataset will be made available to all researchers, enabling more accurate prediction in future. “Our focus so far has been on a prospective influenza pandemic, but this dataset will be valuable in our efforts to understand and control a variety of infectious diseases, both in the UK and in extrapolating to other countries,” said Gog.

“While these preliminary results are eye-opening there’s a lot more this data can be used for,” said programme host Dr Hannah Fry. “Scientists around the country will be using it for years to come.”

̽��ֱ��BBC Pandemic app was launched in September 2017. Once downloaded, app users enter some basic anonymous demographic information about themselves such as age and gender, and then are asked to be tracked via the GPS on their phone once an hour for 24 hours. ̽��ֱ��app also records the people they come into close contact with. This is the first time tracking, demographic and contact data have been combined, making it an unrivalled tool for pandemic research.

̽��ֱ��headline results of the simulation shown in the programme are based on a moderately transmissible influenza pandemic virus with a high fatality rate, in accordance with a ‘reasonable worst case’. ̽��ֱ��details of assumptions and limitations are discussed in detail in the paper.

Reference
Petra Klepac, Stephen Kissler and Julia Gog. ‘Contagion! ̽��ֱ��BBC Four Pandemic – the model behind the documentary.’ Epidemics (2018). DOI: 10.1016/j.epidem.2018.03.003

How fast could a new flu epidemic spread? ̽��ֱ��results of the UK’s largest citizen science project of its kind ever attempted, carried out by thousands of volunteers, predict that 43 million people in the UK could be infected in an influenza pandemic, and with up to 886,000 of those infected expected to be fatalities.

We don’t know of any studies that join up the movement and survey data so comprehensively.

Julia Gog

Geographic patterns of spread of influenza pandemic

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

Yes

Pox populi: Study calculates 18th century syphilis rates for first time

tdk25 — Thu, 14 Sep 2017 05:00:41 +0000

A new study has, for the first time, provided statistical information about the likely rate of venereal disease in a community in 18th century urban England. These rare findings are limited to a single city, but if they are representative of other urban centres, they suggest that the rate of sexually-transmitted infection was both surprisingly high, approximately equal among the two sexes and significantly greater than in rural areas.

Very unusually for a pre-census period, the research succeeded in measuring levels of venereal disease in the city of Chester, as well as its immediate surroundings, during the 1770s. It was carried out by Simon Szreter, Professor of History and Public Policy at St John’s College, ̽��ֱ�� of Cambridge, who used two unique and contemporaneous sources to construct a picture of the rate at which people were contracting syphilis, then known as “the pox”.

He found that STI rates in Chester were surprisingly high. ̽��ֱ��study estimates that in the mid-1770s, approximately 8% of residents of both sexes had been infected with syphilis before the age of 35. ̽��ֱ��estimated infection rate among under-35s in rural communities within a 10 mile radius of the city, however, was a little under 1%.

Such figures contrast with the much lower infection rates of modern times. A recently published report by Public Health England, for example, shows that there were 5,920 diagnoses of syphilis across England as a whole during 2016. Even this is abnormally high; it represents the highest level since 1949 and has led to warnings about cuts to sexual health services.

̽��ֱ��prevalence of sexually-transmitted diseases during the pre-modern era influenced both fertility and mortality rates, and being able to determine the rate of infection potentially allows historians to make better judgements about population change. But sources containing statistical information about STIs before the start of the 20th century are virtually non-existent, and the rate has therefore typically been regarded as incalculable.

Szreter’s study was made possible by the extraordinary coincidence of two unique pieces of evidence – the Chester Infirmary’s admissions register, or “Journal of Patients”, which survives for the years 1773-5, and a census carried out by an eminent local physician, John Haygarth, in 1774.

Although a national census only began in 1801, Haygarth – who in a further coincidence had studied at St John’s College, where Szreter is now a Fellow – was an unusually enlightened practitioner who developed his own census for Chester to calculate the prevalence of different types of disease.

“When I heard about the infirmary records, I thought, bingo!” Szreter said. “We have just enough information from Haygarth to reconstruct the most probable age structure of the City of Chester in 1774 – the middle of the three years for which we also have detailed information about who was entering the infirmary and why.”

“Not many academics have the chance to collaborate in their research environment with an eminent member of their own College who died over 200 years ago. But this brand new research would have been impossible without Haygarth’s highly original older research from the 1770s.”

̽��ֱ��Chester Infirmary recorded 177 cases of “venereal distemper” during the 3 years 1773-5. These would have been treated depending on whether the condition was mild, and therefore likely to have been gonorrhoea (“the clap”), or more serious, and therefore syphilis (“the pox”).

̽��ֱ��gruelling but almost universally-accepted treatment for syphilis involved the continual, supervised application of mercury, which caused patients to produce pints of saliva, supposedly flushing out the venereal poisons. Side-effects included swollen gums, mouth ulcers, and severe halitosis. Typically, the process took at least 35 days.

Because of this, Szreter was able to identify likely syphilitic cases at the infirmary depending on the length of stay among patients reporting a venereal “distemper”. He then compared the figure with a set of age-specific estimates about the size of the at-risk population based on Haygarth’s census. Finally, he was able to make a comparable estimate for the rural population within a 10-mile radius of Chester itself.

Together, the results show that almost exactly 8% of residents in Chester had been infected with what was probably syphilis before they were 35, and that the urban population was approximately 8.65 times more likely to contract the disease compared with people living in the surrounding 290 square miles of countryside.

“It is the first time that we have had any historical statistical evidence like this for sexual disease rates anywhere in Britain,” Szreter said. “ ̽��ֱ��demographic story of this period is defined by mortality and fertility, and rates of venereal disease could of course affect both. But because we haven’t been able to study the impact of STIs, much of the history of British population change has been written as if there wasn’t any.”

Aside from his pioneering census work, John Haygarth is known to have kept detailed patient records, which could provide further, valuable information about medicine and disease at this time. So far, these documents have never been found.

Szreter hopes that they may one day turn up, although his own search – including in the St John’s College archives – has proven fruitless to date. “It’s possible that they were thrown away some time after Haygarth’s death,” he added. “If they were ever discovered, it would be the medical historian’s equivalent of finding Richard III in a car park.”

̽��ֱ��study, Treatment Rates for the Pox in early modern England, is published in the academic journal, Continuity and Change.

̽��ֱ��unlikely coincidence of a local hospital record and a census led by a pioneering physician has enabled the first study charting rates of venereal disease in 18th century England, revealing high infection levels in the city of Chester at this time.

"Because we haven’t been able to study the impact of STIs, much of the history of British population change has been written as if there wasn’t any.”

Simon Szreter

Wikimedia Commons

Detail from plate 5 of Hogarth’s “A Harlot’s Progress”, with the protagonist, Moll, dying of syphilis.

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

Yes

Licence type:

Public Domain

Tiny changes in Parkinson’s protein can have “dramatic” impact on processes that lead to the disease

tdk25 — Tue, 30 Aug 2016 05:59:23 +0000

In a new study, a team of academics at the Centre for Misfolding Diseases, in the Department of Chemistry at the ̽��ֱ�� of Cambridge, show that tiny changes in the amino acid sequence of the protein alpha-synuclein can have a dramatic effect on microscopic processes leading to its aggregation that may occur in the brain, eventually resulting in someone being diagnosed with Parkinson’s Disease.

Alpha-synuclein is a protein made up of 140 amino acids, and under normal circumstances plays an important part in helping with the smooth flow of chemical signals in the brain.

Parkinson’s Disease is thought to arise because, for reasons researchers still do not fully understand, the same protein sometimes malfunctions. Instead of adopting the specific structural form needed to do its job, it misfolds and begins to cluster, creating toxic, thread-like structures known as amyloid fibrils. In the case of Parkinson’s Disease, these protein deposits are referred to as Lewy-bodies.

̽��ֱ��new study examined mutated forms of alpha-synuclein which have been found in people from families with a history of Parkinson’s Disease. In all cases, these mutations involved just one change to the protein’s amino acid sequence.

Although the differences in the sequence are small, the researchers found that they can have a profound effect on how quickly or slowly fibrils start to form. They also found that the mutations strongly influence a process called “secondary nucleation”, in which new fibrils are formed, in an auto-catalytic manner, at the surface of existing ones and thus enable the disease to spread.

̽��ֱ��study stresses that these findings do not explain why humans get the disease. Parkinson’s Disease does not always emerge as a result of the mutations and has multiple, complex causes, which are not fully understood.

Patrick Flagmeier, a PhD student at St John’s College, ̽��ֱ�� of Cambridge, and the study’s lead author, said: “As a finding, it helps us to understand fundamental things about the system by which this disease emerges. In the end, if we can understand all of this better, that can help us to develop therapeutic strategies to confront it. Our hope is that this study will contribute to the global effort towards comprehending why people with these mutations get the disease more frequently, or at a younger age.”

Although people who do not have mutated forms of alpha-synuclein can still develop Parkinson’s Disease, the five mutations studied by the research team were already known as “familial” variants – meaning that they recur in families where the disease has emerged, and seem to increase the likelihood of its onset.

What was not clear, until now, is why they have this effect. “We wanted to know how these specific changes in the protein’s sequence influence its behaviour as it aggregates into fibrils,” Flagmeier said.

To understand this, the researchers conducted lab tests in which they added each of the five mutated forms of alpha-synuclein, as well as a standard version of the protein, to samples simulating the initiation of fibril formation, their growth and their proliferation.

̽��ֱ��first round of tests examined the initiation of aggregation, using artificial samples recreating conditions in which misfolded alpha-synuclein attaches itself to small structures that are present inside brain cells called lipid vesicles, and then begins to cluster.

̽��ֱ��researchers then tested how the different versions of the protein influence the ability of pre-formed fibrils to extend and grow. Finally, they tested the impact of mutated proteins on secondary nucleation, in which, under specific conditions, the fibrils can multiply and start to spread.

Overall, the tests revealed that while the mutated forms of alpha-synuclein do not notably influence the fibril growth, they do have a dramatic effect on both the initial formation of the fibrils, and their secondary nucleation. Some of the mutated forms of the protein made these processes considerably faster, while others made it almost “undetectably slow”, according to the researchers’ report.

“We have only recently discovered the autocatalytic amplification process of alpha-synuclein fibrils, and the results of the present study will help us to understand in much more detail the mechanism behind this process, and in what ways it differs from the initial formation of aggregates.” said Dr. Alexander Buell, one of the senior authors on the study.

Why the mutations have this impact remains unclear, but the study opens the door to understanding this in detail by identifying, for the first time, that they have such a dramatic impact on very particular stages of the process.

Dr. Céline Galvagnion, another of the senior authors on the study, said: “This study quantitatively correlates individual changes in the amino acid sequence of alpha-synuclein with its tendency to aggregate. However, the effect of these mutations on other parameters such as the loss of the protein’s function and the efficiency of clearance of alpha-synuclein needs to be taken into account to fully understand the link between the familial mutations of alpha-synuclein and the onset of Parkinson’s Disease.”

“ ̽��ֱ��effects we observed were changes of several orders of magnitude and it was unexpected to observe such dramatic effects from single-point mutations,” Flagmeier said. “It seems that these single-point mutations in the sequence of alpha-synuclein play an important role in influencing particular microscopic steps in the aggregation process that may lead to Parkinson’s Disease.”

̽��ֱ��full study, which also involves Professors Chris Dobson and Tuomas Knowles, is published in the journal, Proceedings of the National Academy of Sciences.

Reference:

Flagmeier, P. et. al: Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of α-synuclein aggregation. PNAS (2016): DOI: 10.1073/pnas.1604645113

Specific mutations in the protein associated with Parkinson’s Disease, in which just one of its 140 building blocks is altered, can make a dramatic difference to processes which may lead to the condition’s onset, researchers have found.

Our hope is that this study will contribute to the global effort towards comprehending why people with these mutations get the disease more frequently, or at a younger age

Patrick Flagmeier

Image of “amyloid fibrils”; thread-like structures which form after the protein alpha-synuclein aggregates. Plaques (protein deposits) consisting of this protein have been found in the brains of Parkinson ’s Disease patients and linked to disease.

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

Yes

California’s sudden oak death epidemic now ‘unstoppable’ and new epidemics must be managed earlier

jeh98 — Mon, 02 May 2016 19:02:00 +0000

Sudden oak death – caused by Phytophthora ramorum, a fungus-like pathogen related to potato blight – has killed millions of trees over hundreds of square kilometres of forest in California. First detected near San Francisco in 1995, it spread north through coastal California, devastating the region’s iconic oak and tanoak forests. In 2002 a strain of the pathogen appeared in the south west of England, affecting shrubs but not oaks, since English species of oak are not susceptible. In 2009 the UK strain started killing larch – an important tree crop – and has since spread widely across the UK.

In a study published today in PNAS, researchers from the ̽��ֱ�� of Cambridge have used mathematical modelling to show that stopping or even slowing the spread of P. ramorum in California is now not possible, and indeed has been impossible for a number of years.

Treating trees with chemicals is not practical or cost-effective on the scales that would be necessary for an established forest epidemic. Currently the only option for controlling the disease is to cut down infected trees, together with neighbouring trees that are likely to be infected but may not yet show symptoms. “By comparing the performance of a large number of potential strategies, modelling can tell us where and how to start chopping down trees to manage the disease over very large areas,” explains Dr Nik Cunniffe, lead author from Cambridge’s Department of Plant Sciences.

̽��ֱ��authors say that preventing the disease from spreading to large parts of California could have been possible if management had been started in 2002. Before 2002 not enough was known about the pathogen to begin managing the disease. Their modelling also offers new strategies for more effectively controlling inevitable future epidemics.

In close liaison with colleagues from DEFRA and the Forestry Commission, models developed in Cambridge are already an integral part of the management programme for the P. ramorum epidemic in the UK. ̽��ֱ��models are used to predict where the disease is likely to spread, how it can be effectively detected and how control strategies can be optimised.

Sudden oak death is known to affect over one hundred species of tree and shrub, presenting a significant risk to the biodiversity of many ecosystems. ̽��ֱ��death of large numbers of trees also exacerbates the fire risk in California when fallen trees are left to dry out. There is now concern that the disease may spread to the Appalachian Mountains, putting an even larger area of trees at risk.

“Our study is the first major retrospective analysis of how the sudden oak death epidemic in California could have been managed, and also the first to show how to deal with a forest epidemic of this magnitude,” explains Cunniffe.

“Even if huge amounts of money were to be invested to stop the epidemic starting today, the results of our model show this cannot lead to successful control for any plausible management budget. We therefore wanted to know whether it could have been contained if a carefully-optimised strategy had been introduced sooner. Our model showed that, with a very high level of investment starting in 2002, the disease could not have been eradicated, but its spread could have been slowed and the area affected greatly reduced.”

̽��ֱ��model also indicates how policymakers might better plan and deploy control when future epidemics emerge.

“It is a tool by which we can make a better job next time, because it is inevitable that there will be a next time,” says Professor Chris Gilligan, senior author and also from the Department of Plant Sciences. “With this sort of epidemic there will always be more sites to treat than can be afforded. Our model shows when and where control is most effective at different stages throughout a developing epidemic so that resources can be better targeted.”

“It can be tempting for authorities to start cutting down trees at the core of the infected area, but for this epidemic our research shows that this could be the worst thing to do, because susceptible vegetation will simply grow back and become infected again,” explains Cunniffe.

Cunniffe, Gilligan and colleagues found that instead treating the ‘wave-front’ – on and ahead of the epidemic in the direction that disease is spreading – is a more effective method of control. They also found that ‘front-loading’ the budget to treat very heavily and earlier on in the epidemic would greatly improve the likelihood of success.

“Unlike other epidemic models, ours takes account of the uncertainty in how ecological systems will respond and how the available budget may change, allowing us to investigate the likelihood of success and risks of failure of different strategies at different points after an epidemic emerges,” says Gilligan.

“Whenever a new epidemic emerges, controlling it becomes a question of how long it takes for us to have enough information to recognise that there is a problem and then to make decisions about how to deal with it. In the past we have been starting from scratch with each new pathogen, but the insight generated by this modelling puts us in a better position for dealing with future epidemics,” he adds.

̽��ֱ��researchers say that the next step in dealing with well-established epidemics such as sudden oak death is to investigate how to protect particularly valuable areas within an epidemic that – as they have demonstrated – is already too big to be stopped.

̽��ֱ��methodology is already being applied to create related models for diseases that threaten food security in Africa, such as pathogens that attack wheat and cassava.

This research was enabled by funding from the BBSRC, DEFRA, NSF, USDA and the Gordon and Betty Moore Foundation.

Inset image: Extensive control starting in 2002 could have greatly slowed epidemic spread (map shows risk of infection in 2030 under no control on left; control on and ahead of wave-front on right) (Nik Cunniffe).

New research shows the sudden oak death epidemic in California cannot now be stopped, but that its tremendous ecological and economic impacts could have been greatly reduced if control had been started earlier. ̽��ֱ��research also identifies new strategies to enhance control of future epidemics, including identifying where and how to fell trees, as “there will be a next time”.

It is a tool by which we can make a better job next time, because it is inevitable that there will be a next time

Professor Chris Gilligan

David Rizzo

Large-scale tree mortality in northern Sonoma County, California

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

Yes

Opinion: How fruit flies can help keep African scientists at home

Anonymous — Mon, 15 Feb 2016 12:01:02 +0000

̽��ֱ��humble fruit fly is being put to an unusual use in sub-Saharan Africa: it’s being used as bait. Its intended lure? It’s hoped that the tiny creature, whose scientific name is Drosophila melanogaster, can stop the exodus of researchers from Africa.

At the moment most of the biomedical research being done in African laboratories is performed using rats. Now a project called DrosAfrica is underway to promote the use of the fruit fly as a model organism for research into human diseases.

There are several reasons for this. Firstly, rats are far more expensive to keep than fruit flies. As an affordable alternative, the fruit fly requires fewer resources to maintain and not as much expensive preparation for experiments.

Also, as a model system, Drosophila enables researchers to perform sophisticated genetics, live imaging, genome-wide analysis and other state-of-the-art approaches. Drosophila research has identified thousands of genes with human equivalents. This has provided key insights into cancer biology, pathology, neurobiology and immunology.

Drosophila is a prime model organism with tens of thousands of researchers working on every aspect of their biology. This work is aided by electronic open resources such as Flybase and stock centres like the one in Bloomington, Indiana in the US. ̽��ֱ��centre will send Drosophila to any lab in the world for the cost of shipping. These stock centres are funded by governmental grants enabling 100 000s flies to be kept alive in warehouses.

And entire research unit has been built with a focus on understanding a specific aspect of the fly. ̽��ֱ��most famous is called Janelia Farm, founded by the Howard Hughes Medical Institute in the US.

A bigger agenda

̽��ֱ��project that’s using fruit flies as bait for scientists is known as DrosAfrica. It wants to drive the paradigm shift from rats to flies as experimental organisms. To do this, project leaders have organised workshops to share fruit fly techniques with universities and research institutes across sub Saharan Africa.

But there’s more to the work than merely extolling the virtues of fruit flies.

We also try to provide basic equipment such as dissecting microscopes, buffers, slides and antibodies for labelling proteins to facilitate the creation of local research communities. Such strong communities will ultimately be able to provide PhD programmes and research opportunities for African researchers. This will mean students don’t automatically feel they have to emigrate when seeking research opportunities.

Powerful local research programmes will also help to place the continent in the spotlight of international research. This could ultimately lead to a return of expatriates with a strong scientific background.

Activities organised by DrosAfrica: Past and Future

During the last three years, DrosAfrica has organised three workshops at the Institute of Biomedical Research Kampala International ̽��ֱ��-Western Campus, Uganda. Two focused exclusively on the use of Drosophila for biomedical research. ̽��ֱ��other concentrated on image and data analysis techniques.

Attendants and faculty members of the first DrosAfrica workshop ‘Drosophila in Biomedical Research: Affordable AND Impacting!’ (Summer 2013)

̽��ֱ��workshops' participants came from sub-Saharan Africa and included Nigerians, Kenyans, Ugandans and a delegate from South Sudan. They were able to work on several common projects and then networked after the workshops using information and resources on a dedicated website. These interactions planted the seed for developing an African Drosophila research community. At this institute, we’ve been lucky to build on the work that the non-profit organisation Trend has already done. Their team of volunteer scientists equipped the institute’s lab and introduced insect research models to the local scientists.

In 2016 the project plans to deliver workshops at Kenya’s International Centre of Insect Physiology and Ecology. ̽��ֱ��team is also visiting Nigeria during the second half of February to pave the way for future research collaborations.

̽��ֱ��work done over the past few years has already paid dividends. Alumni from the workshops have presented their work at international scientific conferences and supervised undergraduate, Masters and PhD projects. PhD candidates have graduated on the basis of their research done on flies. One student has submitted an abstract to the American Society for Biochemistry and Molecular Biology.

DrosAfrica vision

̽��ֱ��DrosAfrica project is taking important steps to increase the African contribution to scientific advancement. In the coming years we hope to further boost local research opportunities to promote genuine African research led by African researchers, all of them investigating matters of interest to Africans.

And to think: it all started with a tiny little fruit fly.

*DrosAfrica would like to acknowledge the generosity of Faculty members and sponsors, without whom the workshops described above wouldn’t have been possible. They are:

(Cambridge Africa, Sayansi, Wellcome Trust, TWAS, KIU, Pembroke College-Cambridge, St John’s College-Cambridge, Emmanuel College-Cambridge, EMBO, Fruit4Science, and very specially to FRS Tony Kouzarides).*

Silvia Muñoz-Descalzo, Lecturer in Biology & Biochemistry; Developmental Biology Theme, ̽��ֱ�� of Bath and Timothy Weil, Lecturer, Department of Zoology, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Timothy Weil (Department of Zoology) and Silvia Muñoz-Descalzo ( ̽��ֱ�� of Bath) discuss the project that aims to make the fruit fly a model organism for research in Africa.

Tim Weil and Anna York-Andersen, Weil Lab

Actin cables in Drosophila nurse cells during late-oogenesis. At this stage, nurse cells die and extrude their cytoplasm into the developing oocyte.

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Opinion: How close are we to successfully editing genes in human embryos?

Anonymous — Thu, 17 Dec 2015 11:31:23 +0000

An important international summit on human gene editing recently recommended that researchers go ahead with gene editing human embryos, but keep revisiting how and when such modifications would be appropriate in the clinic. ̽��ֱ��decision came after some scientists called for a moratorium on such research.

̽��ֱ��recommendation was always going to be controversial, with many people concerned that the technology, which could be used to prevent parents from passing on genetic diseases to their children, will be misused and lead to permanent changes in the human gene pool.

But how close are we – is there really reason to be concerned at this point?

Laboratory promise

Gene editing of the human germline – those cells that form the sperm and eggs and, from a fertilised egg, will generate every cell in the human body – is different from other types of genetic editing because changes in those cells will be inherited by future generations, to become a permanent change in the human make-up.

Working on human germline cells at the very earliest stages of the formation of an embryo, just after an egg has been fertilised and then implants itself in the womb, is of course impossible to do in a pregnant woman. In my lab, where our focus is on early development, we approach this research using mice and, more recently, by simply growing human cells in a culture dish. In this way we have managed to identify some of the earliest genetic events that “specify” a stem cell to become a germline cell.

At the same time the technology underpinning gene editing, such as the CRISPR/Cas9 – a fast, easy and unprecedentedly precise method for targeting edits to specific genes – is becoming widespread across science. Together with the new ways of studying germline cells in the lab, this is offering a real chance for scientists and the public to consider whether or not editing of the human germline has merit – before any harm can be done.

We can now create human “primordial germ cells”, the precursors to eggs and sperm, from embryonic stem cells. It is a delicate and time-consuming procedure, and the resulting cells do not survive beyond the very early stages of development – partly because we have yet to reproduce the conditions that they are designed to thrive in. What we have been able to show is that some of the earliest steps in the development of human primordial germ cells are different from those in mice. This is important as most of the previous results in this area have come from mouse models, indicating that such information cannot actually be wholly extrapolated to describe humans.

Last year, we also managed to generate primordial germ cells from adult body cells, such as human skin cells. We take body cells that have been programmed to revert back into stem cells, and add chemical factors to “re-specify” them as primordial germ cells.

It is possible to create gene-edited sperm in mice. But humans may be a different story. Gilberto Santa Rosa from Rio de Janeiro, Brazil/wikimedia, CC BY-SA

While these cells don’t survive long either, experiments have shown that introducing such cells into the testes and ovaries of in mice does allow them to continue their development and maturation into sperm and eggs. Remarkably, such mice were able to give birth to healthy offspring raising the prospect of reprogrammed skin cells creating living human beings. For that reason it certainly makes sense to carry out similar studies using primates. Further research might also make it possible to develop working sperm and egg cells entirely in a culture dish.

Finished blueprint?

Looking ahead, it is clear that there already is a potential template for editing the human germline. Genome-sequencing methods could also provide for additional checks to ensure that no inadvertent mutations or “off-target” effects have occurred during the editing procedures.

What’s more, if viable sperm and eggs could be grown in the lab from primordial germ cells, they could be used to generate fertilised embryos. Such “pre-implantation” embryos could also be further screened (as is routine now in the in-vitro fertilisation procedure) to ensure transfer to the womb of only those embryos that are free from specific mutations.

So how could this work in a clinic? Imagine combining the procedures in one patient, for example a woman with a disease-causing mutation who does not wish to pass this mutation to her child. Starting with a cell taken from her skin, this is reprogrammed to a primordial germ cell, in which the DNA is then edited to remove the mutated gene. ̽��ֱ��primordial germ cell is developed into an egg and used to create an embryo for IVF, to be screened and transplanted back into her womb. The child and its subsequent descendants would be free of the mutated gene.

There’s a reason why the summit carefully considered such massive implications and nevertheless recommended to pursue such research. Without making further gains in our knowledge about the fundamental processes in early germ cell and embryo development – starting with growing germ cells for longer in the culture dish – we will not know what we can and cannot safely achieve with the new gene-editing technologies. We are still some way from being able to contribute the necessary biological evidence to society’s debate about which, if any, of these technologies to pursue.

Azim Surani, Director of Germline and Epigenomics Research at the Gurdon Institute, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Azim Surani (Wellcome Trust/Cancer Research UK Gurdon Institute) discusses gene editing of the human germline.

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A human embryo at the blastocyst stage, about six days after fertilization, viewed under a light microscope.

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On the trail of history’s biggest killers

tdk25 — Fri, 06 Mar 2015 06:00:27 +0000

Diseases such as bubonic plague, smallpox, or scurvy, killed so many and caused such misery that they are still household names today, even if for most of us they are things of the past. From an historical perspective, they are also fascinating. By studying these illnesses and their impact, we can understand more about the people for whom such horrors were commonplace and real. Moreover, remarkable and inspiring tales of scientific endeavour are often part of the story of how they were controlled, treated, in some cases cured, and, in the case of smallpox, even eradicated from the globe.

Yet the study of these conditions is about more than simply gleaning historical information from a cabinet of increasingly distant medical curiosities. As time goes by, scientific knowledge is not just informing the work of historians; it is being informed by it. Many modern-day historians of medicine are operating more and more like pathologists and epidemiologists in their efforts to understand what caused the most disastrous pandemics of previous centuries, and how and why they spread. Their work is providing vital new information in the fight against modern-day “plagues”, such as cancer and dementia. More worryingly, it has started to highlight cases where millions died for medical reasons that remain obscure, raising some pressing “what-if” scenarios about our future.

In a new book published this week, Murderous Contagion, the historian of medicine Mary Dobson examines 30 of the biggest killers in the history of humankind, from scourges like the Black Death of the 14th century, to modern epidemics such as HIV/AIDS, and the still-developing Ebola crisis. Rather than simply focusing on the gruesome history of disease itself, however, or the often agonising treatments administered to earlier generations of patients, the study also shows how modern science and the history of medicine have come to depend on each other.

For one thing, historians are now able to take advantage of a growing body of scientific knowledge for their research. We know more than we ever have, for example, about how diseases “jumped” the barriers between species and spilled over from bats, birds, wild and domestic animals to humans, often adapting in their hosts as they spread. New techniques for recovering and analysing ancient DNA are also making it easier to identify past pathogens that were previously mysteries.

As we understand more about historical outbreaks, however, we are also learning more about human susceptibility to certain diseases, and how they might be prevented from recurring. History is increasingly capable of providing modern science not just with a record of what happened, but with information about why.

“Historians of medicine are moving closer to modern science as they come to understand more about the origins of disease,” Dobson, who is based at St John’s College, ̽��ֱ�� of Cambridge, explained. “It’s vitally important to get on top of where and how diseases originate before they have a chance to spread, and history can play an important role in this work. Understanding these stories is important for stopping diseases in their tracks, and fundamental to the goals of advancing global health in the present and future.”

Dobson’s book features striking examples of cases in which historical knowledge has, unexpectedly, become relevant to modern medical practice. In the 1950s, for example, two British epidemiologists decided to investigate the cause of a surge in cases of lung cancer that had become apparent during the previous decades. They predicted that this would most likely turn out to be exposure to car exhaust fumes, or possibly the tarring of roads.

As an outside possibility, they also considered smoking as another potential reason for the spike in cases. Some scientists thought this unlikely, but speculations about a link dated back as far as the 17th century, when James I himself had warned that tobacco was “hateful to the nose, harmful to the brain [and] dangerous to the lungs”. As we now know, smoking was indeed discovered to be the main cause of this emerging tragedy, and public health campaigns on the subject have become more plainspoken and forthright ever since.

̽��ֱ��potential for BSE, better known as “Mad Cow Disease”, to infect humans as variant Creutzfeldt-Jakob Disease (vCJD), might similarly never have become evident without historical knowledge of an obscure condition known as Kuru. This disease, characterised as “the trembling death”, had first been observed in the early 20th century among the indigenous population of Papua New Guinea. Symptoms included involuntary tremors, jerks, uncontrollable outbursts of laughter, loss of co-ordination, wasting and eventually death. ̽��ֱ��brains of people who had died from the disease were found to be riddled with holes. Extensive research eventually posited a link with ritualistic cannibalism, and thanks to the ending of such rites in the mid-20th century, Kuru all but disappeared, vindicating the theory.

These unusual symptoms were also apparent in some animal diseases, such as scrapie in sheep and in BSE in cows. In each case, the brain was found to have become “spongiform”, or Swiss-cheesed with holes. Scientists eventually linked these conditions to a new agent of infection; rather than a virus or bacterium, Kuru, scrapie and BSE were caused by an aberrant protein called a prion.

̽��ֱ��cannibalistic connection that had led to these symptoms emerging in Kuru opened up the disturbing possibility that BSE had emerged due to “high-tech” cannibalism, in the form of cattle feed made of proteins derived from sheep and cattle. By the 1980s, it was not just clear that this had happened, but that scrapie may have made an inter-species jump to become BSE in cows. If that was true, then it was equally possible that a similar leap could occur between cows and humans, particularly when cases of ‘new variant’ CJD started to emerge in young people.

This realisation formed the basis of the mid-1990s scare over BSE and vCJD in Britain. ̽��ֱ��feared large-scale epidemic of vCJD has not materialised, however, partly because offal had already been removed from cattle feed and tight controls put in place to keep infected meat out of the food chain. ̽��ֱ��link to Kuru, and subsequent discovery of prions, was critical: “What had begun as a mysterious disease in Papua New Guinea and an esoteric discussion in scientific circles about the cause of a rare class of animal and human neurological disorders has led to the revolutionary discovery of a new biological principle of infection in the form of prions,” Dobson writes.

In recent times, the story has taken a fascinating new twist as this research has begun to be linked to modern work on neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although these diseases are not infectious, they are, it has emerged, like the Kuru-vCJD family, associated with the “misfolding” and malfunctioning of proteins. There is also growing evidence that the mechanisms by which these diseases progress could indeed be very similar. Even the recent upsurge in cases of type 2 diabetes appears to be linked to this “misfolding” phenomenon.

Elsewhere, the book highlights cases where the identity of the historical causes of a disease could prevent similar disasters occurring. Following the recent outbreaks of avian flu and swine flu, the mystery that surrounds historical pandemics of influenza is of especial concern. In particular, the cause of Spanish Influenza, which killed at least 50 million people between 1918 and 1920 – the highest death toll of any pandemic in human history – was unknown at the time.

Despite being one of the most deadly diseases of all time, Spanish Flu was until recently so little-studied it was sometimes characterised as a “forgotten” pandemic. Now scientists and historians are joining forces to understand how it began, how it spread, and why it was so lethal, especially in young adults. ̽��ֱ��traditional theory that it was disseminated by troop movements during and after World War I fails to explain why some of the worst-affected countries, such as India and Samoa, were far from the main theatres of conflict.

To date, there has been no subsequent global influenza pandemic of such lethality. H5N1 (bird flu), while potentially dangerous, has displayed limited capacity to “jump” the species barrier as initially feared, thereby, hopefully, eliminating any possibility of widespread human-to-human infection. H1N1 (swine flu) in 2009 was a more worrying example of “reassortment”, a process by which different types of flu combine into new strains, but was probably effectively contained through careful screening, quarantine programmes and efficient drug delivery – although not until it had claimed perhaps as many as 200,000 lives.

Both cases, however, demonstrate the urgency with which historians need to understand what caused the far more devastating Spanish flu pandemic. Researchers are now investigating the subject in the hope of finding more answers, and have even gone so far as to exhume the remains of victims from the permafrost to comprehend its cause, with the latest findings suggesting that it might, indeed, have been a novel form of bird flu.

Nonetheless, there are still questions to be asked and solved: “We still don’t know why and how Spanish Flu went global,” Dobson said. “But if we want to stop virulent flu pandemics from happening again, we really need to know more about why they happened in the past.”

Murderous Contagion: A Human History Of Disease by Mary Dobson is published by Quercus on March 6th, 2015.

Lower image shows soldiers from Fort Riley, Kansas, ill with Spanish influenza at a hospital ward at Camp Funston. Credit, Wikimedia Commons.

As well as telling us more about earlier societies, the study of diseases in the past is proving an invaluable tool for modern science, as a new book by the historian of medicine Mary Dobson reveals.

It’s vitally important to get on top of where and how diseases originate before they have a chance to spread. Understanding these stories is important for stopping diseases in their tracks.

Mary Dobson

Wikimedia Commons

Policemen in Seattle wearing masks made by the Red Cross, during the Spanish Influenza epidemic, December 1918.

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