Liston lab

Farewell to Julian Behr

A big farewell to Julian Behr. Julian has been an amazing Masters student this year. Our first Babraham alumni is now off to start his PhD with Maries van den Broek at the University of Zurich. Expect great things!

New horizons for Immunology

by Becky Allen

New group leaders bring new skills, new expertise and new perspectives, and 2018 saw three new group leaders join the Institute’s Immunology programme. Professor Adrian Liston, Dr Claudia Ribeiro de Almeida and Dr Sarah Ross talk about their research, their ambitions and what makes the Institute such a special place to work.

They come from VIB in Belgium, Oxford’s Proudfoot lab and the University of Dundee, they focus on different areas of immunology and bring new interests and expertise, but Professor Adrian Liston, Dr Claudia Ribeiro de Almeida and Dr Sarah Ross are all hugely excited to have recently joined the Institute.

Liston, already an established group leader, works on the specialist population of immune cells known as CD4T cells. These cells effectively coordinate and ‘turbo charge’ our immune response. They are also the cells that are targeted by HIV, explaining why the disease causes immune system suppression and illustrating how crucial CD4T cells are to our overall health.

At VIB, Liston specialised in translational immunology, understanding and then developing ways to treat children with rare immune diseases. “These diseases are incredibly severe, but once you understand them mechanistically you can work out ways to treat them,” he explains. “It was very rewarding because these kids that would otherwise often die can go on to lead long, healthy lives once you’ve found out what’s wrong and how to fix it.”

At the Institute, Liston wants to answer three key questions: how the millions of CD4T cells in our bodies communicate and cooperate; how they switch between a ramping up and damping down cell type; and what they do in our tissues. Understanding how these cells modulate our immune system means that they can potentially be used as a tool to fine tune the immune system to help overcome age-related decline.

With its world-leading Immunology programme and cutting-edge facilities the Institute is a great fit for Liston’s ambitions. But what sets the Institute apart is how it nurtures scientific innovation and champions equality and inclusion.

“Great research requires fantastic people who think as differently as possible, which means having an environment that celebrates equality and inclusion. The Institute has a great reputation for this internationally – it’s setting the gold standard for equality and inclusion. You can feel the difference here,” says Liston. “The Institute provides an environment where you’re going to be stimulated and have the chance to explore the limits of your imagination.”

Ribeiro de Almeida and Ross both believe the Institute’s culture will help them build their first research groups. “It’s a very friendly, supportive environment. Everyone is ready to help with time and feedback – they want you to succeed and that’s really special,” says Ross.

Ribeiro de Almeida’s work centres on B lymphocytes and the rare ability they have to rearrange antibody genes by cutting and pasting DNA in order to fight the plethora of pathogens to which we are exposed. “I’m interested in understanding how this mechanism is regulated throughout cell development,” she explains. “It’s a fundamental question, because mistakes in this process can result in leukaemia and lymphoma. To understand these diseases and wider age-related immune dysfunction it’s important to understand how these molecular mechanisms are regulated.”

As a postdoc in Oxford, she worked in a lab that studied gene expression rather than B cells, so she brings a more molecular approach to the programme. She also discovered an RNA-binding protein that plays an important part in B lymphocytes’ cut and paste process, something she’s keen to follow up: “The research I want to do next is to identify which proteins are implicated in this mechanism of gene rearrangement and how they modulate B cell responses.”

Ross specialises in T lymphocytes and the impact that hypoxia – or low levels of oxygen – has on the way they work. Because T cells commonly encounter hypoxic environments, they can adapt to low oxygen environments by changing the proteins they express. While this helps them survive, it can also make them less effective killers of disease cells.

“I want to understand how oxygen regulates T cells from a signalling and gene expression perspective,” she explains. “If we could identify factors that we could target therapeutically to overcome the effects of low oxygen and boost the ability of T cells to perform their protective function, that would be amazing.”

We know that as we age, our immune system becomes less effective and poorer oxygenation is also connected with ageing, so what Ross discovers about hypoxia could have important implications, both for our understanding of the ageing immune system and in making immunotherapies more successful.

The arrival of all three is an exciting opportunity for the Institute, the Immunology programme and its three new group leaders. “It’s amazing – I’m still pinching myself,” Ross concludes. “It’s great to be able to make new plans and work out how to turn them into reality utilising the know-how and the facilities we have access to here. And it’s exciting to be here because my plans cover all three programmes – Immunology, Signalling and Epigenetics – adding my own to all the expertise here makes it hugely exciting.”

Read online

Golden Pipette won by Dr Wenson Karunakaran

Congratulations to Dr Wenson Karunakaran! 

It was tough competition for the sixth Golden Pipette at the Cambridge-Leuven joint lab retreat. The final prize had to go to Dr Karunakaran for his work on brain CD4 T cells.

Many neuroscientists assume there are no CD4 T cells inside the healthy brain, but there are in fact around 5000 per gram of brain tissue. How do we know? Wenson imaged and counted them, one by one. 

That is what it takes to win the Golden Pipette.

Immune profiling ‘will be a revolution in medicine’

A revolution in medicine is coming.

It could aid the diagnosis of diseases, guide the way patients are treated and inform the discovery of new therapies.

Immune profiling seeks to explain how our body’s own defences are affected by and are responding to disease.

At the Babraham Institute, Professor Adrian Liston is working on the translation of this technique from the laboratory to the clinic.

“The immune profile is much more powerful than genomic data, but it’s much easier to get genomic data,” he tells the Cambridge Independent. “You can take blood, send it overnight and get it sequenced off-site. We are not at that stage with immune system data.

“But the more we know about different diseases, the more we realise there are inflammatory, or immune-mediated, components.

“It can be a revolution in medicine. Once the infrastructure is set up and hospitals are doing the analysis routinely, we will see an explosion in utility. Right now, it’s a research tool only.”

Read the full article at the Cambridge Independent

Using machine learning to diagnose disease

Profiling the immune system in paediatric arthritis patients offers hope for improved diagnosis and treatment

A team of scientists from VIB and KU Leuven has developed a machine learning algorithm that identifies children with juvenile arthritis with almost 90% accuracy from a simple blood test. The new findings, published this week in Annals of the Rheumatic Diseases, pave the way for the use of machine learning to improve diagnosis and to predict which juvenile arthritis patients may respond best to different treatment options. The work was led by Professor Adrian Liston, a group leader at the Babraham Institute in Cambridge, UK and at VIB and KU Leuven in Leuven, Belgium.

Juvenile idiopathic arthritis is the most common rheumatic disease in children, but it presents in many different severities and forms. This diversity makes clinical assessment and patient classification difficult.

A team of researchers at Belgian research organisations VIB, KU Leuven and UZ Leuven undertook a detailed biological characterisation of the immune system of hundreds of children with and without juvenile arthritis to help the diagnosis or treatment decisions for this disease.

“Essentially, we took blood samples from more than 100 children, two thirds of whom had childhood arthritis,” explains Erika Van Nieuwenhove (VIB-KU Leuven), and first author of the study. “We analysed their immune system at a greater level of detail than was ever done before for this disease, and simply using this data we then used machine learning to see if we could tell which children had arthritis.”

The results were quite remarkable: the algorithm was about 90% accurate at identifying the children with the disease. “Using only information on the immune system, and no clinical data at all, we could design a machine learning algorithm that was about 90% accurate at spotting which kids had arthritis,” says Professor Adrian Liston (Babraham Institute, Cambridge, UK and VIB-KU Leuven). “This result is a proof-of-principle demonstration that immune phenotyping combined with machine learning holds huge potential to diagnose disease. Similar approaches could be applied to improve patient selection for treatments and clinical trials.”

The researchers are hopeful about the impact of this research in improving patient outcomes. “The tool needs further validation but otherwise there are no scientific barriers to this approach being quickly translated to the clinic,” comments Professor Carine Wouters (UZ Leuven), who was the clinical lead for this study. “Down the line, we could use this kind of detailed classification information—and machine learning analysis—to identify which patients will respond best to specific treatment options.”

Front cover of Blood

Our study on myeloproliferative disorder is on the front cover of Blood

Farewell to John Barber

Sad to see John Barber leaving us to go back to his medical degree. He has spent the last year uncovering a novel genetic cause of neutropenia - details to follow soon!

Best of luck John, you'll be missed!

Congratulations to Prof Humblet-Baron!

Congratulations to Dr Stéphanie Humblet-Baron, who was just awarded the prestigious (and highly competitive) BOF-ZAP award. With this award Stéphanie starts a tenure-track research professorship and her own independent group.

The success of both Prof Humblet-Baron and Prof Schlenner at the BOF-ZAP awards puts the Translational Immunology laboratory in a great position. Going forward from my move to the Babraham, Prof Schlenner is leading the mouse immunology research and Prof Humblet-Baron is leading the clinical immunology research program.

Leaving two such talented and determined women to take over my lab, and push it to new heights, is my proudest legacy of 10 years in Leuven.

The Humblet-Baron team will develop and use cutting-edge systems immunology approach to study the many diseases in which the immune system places a key role, from primary immunodeficiency to infections to cancer to neurodegeneration. Watch out for great things new Prof Humblet-Baron is here!

Identical twins light the way for new genetic cause of arthritis

Identical twin girls who presented with severe arthritis helped scientists to identify the first gene mutation that can single-handedly cause a juvenile form of this inflammatory joint disease. By investigating the DNA of individual blood cells of both children and then modelling the genetic defect in a mouse model, the research team led by Adrian Liston (VIB-KU Leuven) was able to unravel the disease mechanism. The findings will help to develop an appropriate treatment as well.

Juvenile idiopathic arthritis is the most common form of all childhood rheumatic diseases. It is defined as arthritis that starts at a young age and persists throughout adulthood, but which does not have a defined cause. Patients present with a highly variable clinical picture, and scientists have long suspected that different combinations of specific genetic susceptibilities and environmental triggers drive the disease.

A single gene mutation

In a new study by researchers at VIB, KU Leuven and UZ Leuven, the cause of juvenile arthritis in a young pair of identical twins was traced back to a single genetic mutation.

"Single-cell sequencing let us track what was going wrong in every cell type in the twin’s blood, creating a link from genetic mutation to disease onset,” explains Dr. Stephanie Humblet-Baron, one of the researchers involved in the study. “It was the combination of next generation genetics and immunology approaches that allowed us to find out why these patients were developing arthritis at such a young age.”

Of mice and men

Parallel studies in mice confirmed that the gene defect found in the patients’ blood cells indeed led to an enhanced susceptibility to arthritis. Prof. Susan Schlenner, first author of the study, stresses the relevance of this approach: "New genetic editing approaches bring mouse research much closer to the patient. We can now rapidly produce new mouse models that reproduce human mutations in mice, allowing us to model the disease of individual patients."

According to immunology prof. Adrian Liston such insights prove invaluable in biomedical research: “Understanding the cause of the disease unlocks the key to treating the patient.”

From cause to cure

Liston’s team collaborated closely with prof. Carine Wouters, who coordinated the clinical aspect of the research: "The identification of a single gene that can cause juvenile idiopathic arthritis is an important milestone. A parallel mouse model with the same genetic mutation is a great tool to dissect the disease mechanism in more detail and to develop more effective targeted therapies for this condition.”

And the little patients? They are relieved to know that scientists found the cause of their symptoms: "We are delighted to know that an explanation has been found for our illness and more so because we are sure it will help other children."

Thankfully, the children’s arthritis is under good control at the moment. Thanks to the new scientific findings, their doctors will be in a much better position to treat any future flare-ups.

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology 

Schlenner et al. 2018 Annals of the Reumatic Diseases