̽��ֱ�� of Cambridge - Tim Cox

Rare genetic disease may protect Ashkenazi Jews against TB

cjb250 — Mon, 06 Feb 2023 20:00:02 +0000

In research published today in Proceedings of the National Academy of Sciences (PNAS), Cambridge scientists – with colleagues in the Netherlands, Spain, and Pennsylvania, USA – show that the same biological mechanisms that underlie Gaucher disease are also effective at clearing TB infection.

̽��ֱ��discovery – made while studying TB susceptibility in zebrafish – suggests that genetic variants that increase the risk of Gaucher also help protect against TB, giving them a selective advantage – that is, making the variants more likely to be passed down from generation to generation.

In 2021, an estimated 10.6 million people worldwide fell ill with TB and 1.6 million people died from the disease. Most people manage to clear the infection themselves, however – only around one in 10 to 20 people will go on to develop the disease.

Professor Lalita Ramakrishnan and colleagues from the ̽��ֱ�� of Cambridge and the Medical Research Council Laboratory of Molecular Biology, Cambridge, are interested in what makes some people susceptible to TB while others appear to be protected. She uses zebrafish to model human disease as it is relatively easy to manipulate zebrafish’s genetics, and their immune systems share many similarities with those of humans.

During their research, her team had previously found that zebrafish with mutations that impaired the digestion of proteins by lysosomes became more susceptible to TB. Lysosomes are components of our cells that break down unwanted materials, including proteins and fats, using enzymes. When a mutation affects the production of these enzymes, it can lead to a build-up of toxic materials.

One type of cell that is vulnerable to this build-up is the macrophage, a type of immune cell that ‘eats’ toxic material, including bacteria and waste products. In lysosomal disorders, the macrophages become enlarged because of accumulation of undigested material in their lysosomes and move slowly, hampering their ability to fight infection.

Professor Ramakrishnan said: “Macrophages need to move quickly to attack invading bacteria and viruses. Their name means ‘big eater’, and this is exactly what they do. But with lysosomal disorders, they’re unable to break down the food they eat, which makes them bloated and sluggish, unable to perform their duties.”

However, when Ramakrishnan and colleagues modelled a lysosomal storage disease known as Gaucher disease, they found something very unexpected: TB resistance rather than susceptibility.

Gaucher disease is a rare disease, affecting around one in 40,000 to 60,000 births in the general population, but rates are significantly higher among Ashkenazi Jews – around one in 800 births. In most cases, the disease can be relatively mild – with symptoms including enlarged spleen and liver, and anaemia – and around two-thirds of people carrying two copies of the most common genetic variant are unaware they are carriers.

When the researchers genetically engineered zebrafish with genetic variants causing Gaucher disease that are common among Ashkenazi Jews, as anticipated their macrophages became enlarged and unable to break down the toxic materials, in this case an unusual type of fat (called sphingolipids) rather than protein. But when the team exposed the fish to TB, they discovered unexpectedly that the fish were resistant to infection, not susceptible.

̽��ֱ��reason for this resistance to infection was because of the fatty chemical that accumulates within the macrophages in Gaucher disease, called glucosylsphingosine. Glucosylsphingosine was found to act as a detergent-like microbicide that kills TB mycobacteria within minutes by disrupting their cell walls.

Professor Ramakrishnan added: “We’d unknowingly landed in a debate that’s been going on in human genetics for decades: are Ashkenazi Jews – who we know are at a much greater risk of Gaucher disease – somehow less likely to get TB infection? ̽��ֱ��answer appears to be yes.”

̽��ֱ��Ashkenazi Jewish diaspora has experienced centuries of persecution, often forced to live in ghettos and migrate from country to country. They would almost certainly have been exposed to TB, which spreads more widely among poorer living conditions and densely-populated urban areas.

Although this genetic mutation is associated with Gaucher disease, the fact that it makes people more resistant to TB would likely have outweighed the potential fitness cost of Gaucher disease. This would have increased the likelihood of affected individuals passing on their genes to future generations and therefore spread the mutation within the population. A similar phenomenon is seen among some individuals who carry genetic variants that protect them from malaria but, when more than one copy is present, cause harmful anaemia or even sickle cell disease.

Unlike the example of sickle cell anaemia, however, only individuals who carry two copies of the Gaucher genetic variant – one from each parent – are likely to be protected against TB. That’s because the one ‘healthy’ gene generates enough of the enzyme to clear the macrophages of their accumulating material – and hence gets rid of the antimicrobial substrate.

Professor Timothy Cox from the ̽��ֱ�� of Cambridge, a co-author on the paper, added: “Our discovery may provide clues to possible new treatments for TB. Drugs that mimic the effects of Gaucher disease – specifically the build-up of glucosylsphingosine – might offer antimicrobial effects against TB.”

Several such drugs have already been designed by Professor Hans Aerts from Leiden ̽��ֱ��, another co-author on the paper. Because these drugs would only need to be administered for a relatively short amount of time, any side-effects should be limited and temporary.

̽��ֱ��research was funded by Wellcome, Gates Cambridge and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Reference
Fan, J et al. Gaucher Disease Protects Against Tuberculosis. PNAS; 6 Feb 2023; DOI: 10.1073/pnas.2217673120

Scientists may have solved the question of why Ashkenazi Jews are significantly more susceptible to a rare genetic disorder known as Gaucher disease – and the answer may help settle the debate about whether they are less susceptible to tuberculosis (TB).

We’d unknowingly landed in a debate that’s been going on in human genetics for decades: are Ashkenazi Jews somehow less likely to get TB infection? ̽��ֱ��answer appears to be yes.

Lalita Ramkrishnan

halbergman (Getty Images)

Grandfather Helping Little Boy to Wash His Hands at Passover Seder with Family - stock photo

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Vice-Chancellor’s awards showcase Cambridge researchers' public engagement and societal impact

Anonymous — Mon, 09 Jul 2018 15:26:38 +0000

Hundreds of post-war peace settlements were trawled through by a team at Cambridge’s Lauterpacht Centre for International Law to build this innovative research tool. Outputs from the work have been used to assist mediators engaged with some of the world's most violent and tragic conflicts.

̽��ֱ��announcement was made at a prize ceremony held at the Old Schools on 9 July, during which a number of other awards were also presented to Cambridge researchers for projects that have made significant contributions to society – including work on prisons, pandemics, and pollution.

Professor Stephen Toope, Vice-Chancellor of the ̽��ֱ�� of Cambridge, says: “This award scheme, now in its third year, received nearly a hundred nominations from all areas of research within the ̽��ֱ��, which were of an extremely high calibre across the board.”

“Impact is at the heart of the ̽��ֱ��’s mission. Engaging the public is crucial to helping our ̽��ֱ�� deliver on its mission, and to be a good citizen in our city and community. Institutions such as ours have a vital role to play in restoring trust and faith in expertise and ways of knowing.”

Vice-Chancellor’s Impact Awards

̽��ֱ��Vice-Chancellor’s Impact Awards were established to recognise and reward those whose research has led to excellent impact beyond academia, whether on the economy, society, culture, public policy or services, health, the environment or quality of life. Each winner receives a prize of £1,000 and a trophy, with the overall winner – Prof Marc Weller from the Faculty of Law – receiving £2,000.

This year’s winners are:

Overall winner: Marc Weller (Faculty of Law)

Making and sustaining international peace

Drawing on a ten-year research programme addressing self-determination and ethnic conflicts, the Legal Tools of Peace-making project presents, for the first time, the vast practice revealed through peace agreements on an issue-by issue basis, making it instantly accessible to practitioners and academics.

̽��ֱ��project, led by Weller, uses this repository to derive realistic settlement options for use in actual peace-negotiations, and making these available to the United Nations, the African Union, the EU and other mediating agencies. ̽��ֱ��work has had immediate impact on on-going, high-level peace negotiations in the inter-ethnic negotiations in Myanmar, the UN-led negotiations on Syria, discussions on Catalonia, the independence of Kosovo, Sudan and South Sudan, Somalia and several others.

Marko Hyvönen (Department of Biochemistry)

Production of growth factors for stem cell research

‘Growth factors’ are proteins that regulate many aspects of cellular function – including proliferation. These complex proteins are essential for stem cell research, to differentiate stem cells into the specific cell types found in our bodies.

Hyvönen and colleagues have used their expertise as structural biologists to develop methods to efficiently produce growth factors in extremely high quality: reducing cost to the stem cell community locally, and facilitating world-class research. They have spun out a company to supply these proteins for researchers around the globe and secured an Innovate UK grant for the company.

Ryan Williams (Centre of Islamic Studies)

Re-imagining Citizenship

Williams’ research on Islam and society works on the borderlines of religious studies and criminology, challenging practitioners and policy-makers to think holistically about social inclusion and the role of religion in contemporary society.

His research has been incorporated into: guidelines on countering prison radicalisation, adopted by the European Commission in 2017; the evidence base for the Lammy Review on equality and implementing its recommendations; a course on the Good Life Good Society, adopted in 2016 in a high security prison. Read Ryan's This Cambridge Life here.

Florin Udrea (Department of Engineering)

Cambridge CMOS Sensors

Sensors that sniff the air can warn us of pollution in city streets, offices and homes. Breathe on these sensors and they can check our health. But they are normally big, heavy and drain batteries quickly.

Florin Udrea and his team set out to create environmental micro-sensors that are ultra-efficient and small enough for smart phones, watches and air purifiers in smart homes. Their spin-off, Cambridge CMOS Sensors, was acquired by AMS in 2016, which is now shipping products.

Julia Gog (Department of Applied Mathematics and Theoretical Physics)

Harnessing mathematics to help control influenza

Predicting the evolution of the seasonal human influenza virus to better inform vaccination selection is critical to controlling the spread of influenza each year. Moreover, a rarer global outbreak pandemic would have severe consequences on loss of life and the economy, and is viewed by the UK government as a major threat to the UK due to both its high likelihood and severity of outcome.

Julia Gog worked with data gathered through the BBC’s Pandemic project to produce mathematical modelling that helps predict how UK populations move and interact, and consequently how and where a virus would spread.

Tim Cox (Department of Medicine)

Innovative Treatments for Lysosomal diseases

Niemann-Pick C, Tay-Sachs, Sandhoff and Gaucher diseases are genetic lysosomal diseases that affect several organs, including the brain, resulting in painful symptoms, neurological complications and early death. Tim Cox is a leading UK clinical investigator for Lysosomal diseases, exploring the rebalancing of excess production of the toxic sphingolipids, which cause these diseases.

His work has developed effective treatments that have been introduced into the clinic, improving patient outcomes. This research has also identified a definitive correction of the cruel children’s condition, Tay-Sachs disease, through gene transfer. After successful preclinical work, a ̽��ֱ�� spin-out, Cambridge Gene Therapy, is accelerating the clinical programme for this disease.

Vice-Chancellor’s Public Engagement with Research Awards

̽��ֱ��Vice-Chancellor’s Public Engagement with Research Awards were set up to recognise and reward those who undertake quality engagement with research. Each winner receives a £1000 personal prize and a trophy. This year’s winners are:

Sophie Seita (Faculty of English)

Seita produced a collaborative multi-media creative project that combined experimental performances, lecture performances, poetry, publications, and installations; both emerging from and feeding back into research. Presented as star-gazing conversations with a number of Enlightenment writings in English, French, and German, from tragedies, melodramas, philosophical treatises to proto-romantic romances of the period, the work investigates which aspects of the Enlightenment still speak to us today, and was performed at the ̽��ֱ��’s Festival of Ideas.

Anna Spathis and Stephen Barclay (Department of Public Health and Primary Care)

Fatigue, an extreme tiredness that affects the mind as well as the body, is the single most common and distressing symptom experienced by teenagers and young adults with cancer. Spathis and Barclay worked with these young patients to co-design a treatment for fatigue that meets their unique needs. Read Anna and Stephen discuss how public involvement contributed to the research outcomes here.

Charlotte Payne (Department of Zoology)

Working together with farmers and scientists at every stage, Payne developed a participatory research project on the sustainable use of edible caterpillars in southwestern Burkina Faso, and has explained the methods, aims and results to a variety of public audiences of all ages and backgrounds. Read Charlotte discussing edible insects on the BBC here.

Ragnhild Dale (Scott Polar Research Institute)

Dale was a researcher and assistant dirtector on a three-day staging of a mock trial version of the ground-breaking lawsuit where Norwegian environmental organisations Greenpeace and Nature and Youth are suing the Norwegian Government for allegedly allowing unconstitutional oil exploration in the Barents Sea. ̽��ֱ��project inviting expert witnesses from academia, industry and NGOs to testify in our production in Kirkenes, bringing the drama of the trial directly to the people who live and work in the north.

̽��ֱ��first major repository of legal practices for mediators and conflict parties to draw on when negotiating peace has won the top prize in this year’s Vice-Chancellor’s Impact Awards at the ̽��ֱ�� of Cambridge.

Impact is at the heart of the ̽��ֱ��’s mission

Stephen Toope

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