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Entries by Adrian Liston (464)

Friday
Feb082019

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!

Thursday
Jan242019

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

Monday
Dec312018

Advice for international faculty entering the Belgian system

After 10 years in Belgium as a foreign academic, I was reflecting on what lessons I had learned about Belgian academia that I wish I had learned earlier. The key lesson I wish someone had taught me is that Belgian academia works via the patronage system. Having come from the Anglo meritocracy system, it took me a long time to distinguish the features of patronage, as opposed to nepotism or just plain corruption. The system is based on patrons and their protegés, and is so embedded throughout the system that nearly everyone is both a patron and a protegé, in one large network of obligations. One you understand this, many previously inexplicable behaviours and patterns make sense, and it is possible to thrive.

The patron is the "godfather". Patrons do not give orders. They make their wishes known, and they expect their protegés to follow them. In the worst cases, this is exploited simply to further the career of the patrons (by making them successful in the eyes of their own patron). It is expected that the rise of the patron trickles down to the protegé, however it is understood that years or even decades can elapse in between. The patron will also have multiple protegés at the same stage, competing for the spoils of the patron. A highly successful patron may pull up multiple protegés through the system with them, but often it is just the one leading protegé who benefits (and may end up becoming patron to the other protegés). This gives the scenario, rather perplexing to an outsider, of good people putting their patron ahead of themselves year after year, without any benefit. In the best cases, the system can work better than an open merit-based system. Merit-based system work based on track-record, and assume that someone with a good record and a winning interview style will be successful in the position. By contrast, the relationship between patron and protegé is far more intimate, and a patron can ideally identify the person who would be best at the job, beyond the confounding luck and personality issues that can sway a CV or interview. In practice, the worst case scenario seems rather more common than the best case scenario.

The protegé is expected to follow the lead of the patron throughout their career, even after they have reached equivalent levels. The level to which this deference is given is quite remarkable to an outsider. The protegé, even as an independent academic, will follow the guidance of their patron is terms of who they should collaborate with, which grants they should submit, authorship order on papers and key financial decisions. Even when they strongly disagree with the advice, the protegé is more likely to get frustrated in private than to argue (or even ignore) their patron. It would take a really gross violation by the patron for the protegé to break off the relationship. Protegés will take on protegés of their own, becoming a patron to others while still remaining a protegé to their own patron. This creates a "family", with the überpatron at the head. The überpatron respects the downwards hierarchy, however, working via their direct protegés only.

There are aspects of patronage to every academic system, however the key to understanding Belgian academia is to realise that patronage permeates every facet. The degree to which the rules of the patron-protegés relationship are embedded in the Belgian character is difficult to overstate, and even Belgians that have become internationalised may struggle to not default into the pattern. The breakdown of the patron-protegés relationship is very rare, and invokes a deep sense of betrayal.

In practical terms, what does this mean for a foreigner entering Belgian academia?

First, as a foreigner you are unlikely to have a strong patron. For myself, after 10 years in Belgian, I never had a patron.  Admittedly, I am very poor protegé material, but the strongest patronage relationships are formed very early, through family or family friends. Even without having your own patron, however, your Belgian students may instinctively fall into the protegé role, and expect the patron-protegé relationship to function. 

Second, to some extent you need to chose between looking crass or being overlooked. Belgians do not put themselves forward, and self-promotion is considered coarse. It is the role of your patron to promote your virtues or ideas. Without a patron, you can either push yourself forward or be ignored. Self-assertion can still work, and is tolerated more in foreigners than in Belgians, but it won't make friends.

Third, breaking into collaborative networks is going to be difficult to you. Many collaborative grants and projects are built around the patron-protegé networks. Trying to join can be looked upon as nearly akin to crashing a family reunion. Some überpatrons are highly xenophobic, and you will never be allowed in. This can lead to frustration, where a good relationship with a colleague never blossoms into a collaboration, not because they don't want to work with you, but because their own patron disapproves. The best path to breaking into the collaborative networks lies in identifying a more liberal überpatron, and getting adopted into the family. Offering up a new technology or the like can be sufficient to get you adopted, for the advantage that it brings in. Adoption does depend on at least tacitly respecting the hierarchy: the network is not a collection of independent equals, and directly approaching protegés can be taken as highly disrespectful by überpatrons.

Fourth, respecting the hierarchy does not just apply to collaborative networks. Belgian academics would never directly approach one of your students or staff with a question, and expect the same "courtesy" from you. Even students from neighbouring labs don't *officially* talk to each other, and even trivial requests for help are expected to go up to their promoters for consultation first. This feels needless and inefficient, but ignoring the protocol is worse: a faux pas can shutdown relationships with your neighbours for good.

Fifth, you need to understand that arguing in a meeting is normally fruitless. Despite being in hundreds of management meetings over the past 10 years, I've never seen a question go to an actual vote, or even anything approximating a vote. The überpatrons in the meeting know who dominates based on who is in the meeting. To force protegés to openly support their patrons would be the height of rudeness - the system is built on implicit support, not explicit support. Decisions are made before the meeting, either between the überpatrons directly, or via jockeying to stack the meeting with their protegés. I never managed to suppress my instinct to give my opinion at meetings, even when it was clearly against the position of the überpatrons, but even if others at the meeting secretly agree with you it just ends up making you look obnoxious. The more successful approach is to identify the dominant network in advance (not difficult, the chair is usually the leading überpatron), and discuss with them before the meeting. Überpatrons can be thoughtful and consultative, as long as you approach them in private: changing their mind after a public disagreement results in too much loss of face.

Sixth, be highly sensitive to suggestions to place specific people in a position. If you are trying to get a position opened up to fill an unmet need, the actual person who will end up being recruited is typically of secondary importance to you. Open the position, and then find the best person to fill it. For many Belgian academics, however, the actual person who will be recruited is the key point. Getting their protegés positions is the key function of a successful patron. If a Belgian academic listens to your proposal and then suggests one of their protegés for the position, what they are often proposing is a deal: I would support this proposal if my person gets the position. If you dismiss the proposal as downstream, then the patron will think that either you are trying to open the position for your own protegé, or you have an agreement with another patron. The strategic design of proposals to incorporate a protegé from a key überpatron can often lead to success (assuming the protegé would actually be suitable for the position).

Finally, this should be read not as an attack on the Belgian system, but rather as an explanation of how it functions, as discovered by an initially clueless outsider. For Belgian readers, while they would certainly recognise the behaviours, they would probably be rather appalled to see it written in this way. This is not a codified behavior or quid pro quo; it is just how to be polite and respectful to your colleagues and, especially, your seniors. While it can be infuriating at times, and I've occasionally come home fuming about corruption and xenophobia, that is entirely because I was not raised with these same cultural preconceptions. It is surely no worse than the cultural shock of entering the American system, where entirely different sets of rules are at play, and even though they are invisible to me, Australian academia surely has cultural quirks that offend the sensibilities of outsiders. You don't have to embrace the Belgian system, or become part of it, but at the very least you should understand it and respect it enough to not be *unintentionally* obnoxious.

 

Thursday
Dec202018

Stephanie Humblet-Baron tackles one immune disease after the other

In two recent studies, the same team of scientists has uncovered the mechanisms underlying two distinct immunological disorders affecting both children and adults. Stephanie Humblet-Baron(VIB-KU Leuven) was the researcher at the helm of both projects.

A pediatrician by training, Stephanie Humblet-Baron is building a career unravelling immunological disorders that affect children. She divides her time between the clinic and the lab, where she is a senior team leader in the lab of Adrian Liston (VIB-KU Leuven).

From disease to biology and back again

Ever since the start of her medical training, Humblet-Baron developed a special interest in unraveling the biological mechanisms that cause immunological problems. Many immune diseases are poorly understood, and this lack of knowledge also limits treatment options and choices.

“People sometimes refer to these diseases as rare,” says Humblet-Baron, “but we all carry risk factors for many immunological diseases. Even if a given mutation is rare, the accumulated variation in immunological responses affect a broad set of outcomes, for example how someone responds to cancer treatment or drugs for cardiovascular conditions. That is why understanding the mechanisms underlying immune-dysregulation is so important.”

In her most recent work, Humblet-Baron, together with her colleagues in the lab of Adrian Liston (VIB-KU Leuven), focused on the mechanisms causing myeloproliferative disease and hemophagocytic lymphohistiocytosis, two diseases that are fatal unless given aggressive treatment.

Myeloproliferative disorder: a partner in crime for dendritic cells

Dendritic cells are specialized antigen-presenting cells that play a crucial role in coordinating innate and adaptive immune responses. In both patients and mice, depletion of dendritic cells leads to myeloproliferative disorder, but how or why—no one really knew.

“To understand what was going wrong, we created a mouse model where dendritic cells were present in normal numbers, but were functionally impaired,” explains Humblet-Baron. “We found that without the antigen-presenting capacity of dendritic cells, the mice developed myeloproliferative disorder.”

The team uncovered that it was not the number of dendritic cells, but their partnership with CD4 T cells of the immune system that was crucial for disease development. When CD4 T cells were absent as well, the mice showed no symptoms of myeloproliferative disease.

This has important implications for patients, where specific mutations also manifest both dendritic cell deficiency and myeloproliferative disorder. “Based on the original model disease model, the proposed line of treatment would be dendritic cell replacement, currently only possible through bone-marrow transplantation,” says prof. Adrian Liston. “But these new results indicate that attenuating the activatory signal from CD4 T cells could also reduce the development of myeloproliferative disorder.”

Hemophagocytic lymphohistiocytosis: New light on a deadly disease

Hemophagocytic lymphohistiocytosis, HLH for short, is a severe disease less than 2 out of 3 patients survive. It can be triggered by a variety of factors, including genetic defects, viral infections, anti-tumor responses or unchecked autoimmunity. Excessive production of interferon γ was assumed to be the key pathological step, but based on patient evidence and a pre-clinical mouse model of the disease, the Leuven research team has now found that there is much more to it.

Humblet-Baron: “We found that the production of interferon γ was only responsible for part of the features of the disease. Excessive consumption of the immune signaling molecule interleukin 2 by hyperactivated CD8 T cells, the suppressor cells of our immune system, had a much greater impact on the inflammation.”

This means that at least two different disease pathways are at play—knowledge that indicates that we could save the lives of more patients if we also targeted both pathways during treatment.

“This study not only provides a new paradigm for understanding HLH, with major implications for its treatment, but also gives us a broad insight into how hyperactivated CD8 T cells cause damage,” adds prof. Adrian Liston.

“We can learn so much from an in-depth analysis of the immune cells present in a simple sample of blood from patients,” concludes Humblet-Baron, who hopes to uncover the mechanisms underlying many more of these immunological problems. “Coupled with the power of biochemical and animal research, these insights are really changing how we diagnose and treat patients in the clinic.”

 


Humblet-Baron, et al 2018 Blood. "Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells"

Humblet-Baron et al. 2018 Journal of Allergy and Clinical Immunology. "IFN-γ and CD25 drive distinct pathological features during CD8 T cell hyperactivation in hemophagocytic lymphohistiocytosis"


 

Thursday
Dec132018

The genetics behind immune system variation

Tuesday
Dec112018

Golden Pipette won by Steffie Junius

Congratulations to Steffie Junius, the first PhD student to win the Golden Pipette!

Dr Carly Whyte had to relucantly hand over the Golden Pipette to Steffie Junius, in recognition of her pioneering experiments on regulatory T cell fate-mapping.

This means the Golden Pipette will stay in Leuven for now, but the Babraham Team is building up to take back the pipette in 2019!

Monday
Dec102018

Celebrating 10 years of the Liston lab!

Wednesday
Nov282018

FWO funding for Prof Susan Schlenner

Congratulations to Prof Susan Schlenner who secured FWO funding today for a four year project on regulatory T cells! FWO is highly competitive and it is very rare for an applicant to be successfully funded on their first independent application. A sign of future success!

Thursday
Nov152018

Topics we work on

Wednesday
Nov142018

Unlocking The Secrets Of A Rare Immune Disease

by Adrian Liston and Josselyn Garcia-Perez 

Primary immunodeficiencies (PID) are a heterogeneous group of disorders that disturb the host’s immunity, creating susceptibility to infections. PIDs are genetically diverse, with mutations in many different genes capable of causing immunodeficiency. The clinical symptoms of PIDs include, but are not limited to, susceptibility to infections, inflammation, and autoimmunity, although each gene mutated, and indeed each individual mutation, can lead to different manifestations.

Central to understanding PIDs is to understand which immune cell type is rendered defective by the mutation the patient carries. The type of infections the patient develops is often a key indicator of the underlying immunodeficiency; for example, pulmonary infections and bacterial septicemia are associated with B cell defect, whereas fungal susceptibility is associated with defects in certain types of T cells. Candidate pathways can be investigated using genetics and immune screening, and successful identification of the underlying causes allows a treatment program to be tailored to the patient.


Read the full story on Science Trends