Faculty position opening up in Leuven

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Autoimmune Genetics Laboratory in the news

De Standaard, 29-11-2012:

(English translation below)

De sfeer is hier collegialer' - Brain Gain

De Australiër Adrian Liston (32) werkt als hoofddocent immunologie voor de KU Leuven en als onderzoeker aan het VIB. ‘Ik had dubbel zoveel kunnen verdienen in de VS of Australië, maar dat is niet doorslaggevend.'

‘Wij zullen hier nog lang blijven, ja. België is een goede plek om aan onderzoek te doen en om onze zoon op te voeden.'

Bent u uiteindelijk tevreden met uw keuze voor België?

‘Het zou duidelijker moeten zijn dat je je werk in het Engels kunt doen. Publicaties, congressen, lessen,... het gebeurt allemaal in technisch Engels in onze branche.'

‘Ook de taal schrikt misschien af. Aan de KU Leuven moet je op papier in het Nederlands lesgeven, dat werkt drempelverhogend. In de praktijk kan je wel in het Engels lesgeven, zeker in de hogere graden. Maar dat weet een buitenlander niet.'

‘Academische vacatures mikken hier nog heel specifiek op de Belgische markt, ze worden vaak zelfs alleen intern uitgeschreven. Universiteiten zijn hier minder internationaal georiënteerd.'

‘Ik heb gestudeerd aan de Australian National University van Canberra en heb daarna een tijd gewerkt aan de University of Washington in Seattle', zegt Adrian Liston. Hij kreeg aanbiedingen uit Canada, Australië, Ierland, het Verenigd Koninkrijk en België.

Waarom is het België geworden?

‘Omdat het Vlaams Instituut voor Biotechnologie (VIB) zeer actief is in het rekruteren van internationale toponderzoekers. Ik was op zoek naar een plek waar ik onderzoek van het hoogste niveau kon doen. België leek me ook een aangenaam land, met een open houding tegenover mensen die Engels spreken. Ik vind hier ook een goed evenwicht tussen werk en vrije tijd.'

Ziet u verschillen in het academisch klimaat in België en pakweg de VS?

‘De sfeer is hier collegialer, omdat academisch onderzoek veel meer een kwestie van samenwerken is. Wie met buitenlandse onderzoeksgroepen samenwerkt, wordt daar financieel voor beloond. In de Verenigde Staten is het eerder belangrijk wat je als individu verwezenlijkt.'

‘Ik had ongeveer dubbel zoveel kunnen verdienen in de VS of in Australië. Het salaris van een senior researcher ligt best laag in België. Maar ik denk niet dat zoiets doorslaggevend is. De meeste academici willen vooral voldoende geld om aan research te doen. En op dat vlak doet België het tegenwoordig net heel goed.'

‘Er wordt ondanks de crisis niet drastisch gesnoeid in onderzoeksfondsen, in tegenstelling tot in Amerika. Als een academicus echt op zoek is naar een exuberant loon, zoekt hij het in de private sector.'

Wat kan een buitenlandse onderzoeker toch tegenhouden om hier te werken?

'Wij zullen hier nog lang blijven, ja. België is een goede plek om aan onderzoek te doen en om onze zoon op te voeden.'

 A rough English translation:

The atmosphere here is more collegial  - Brain Gain

The Australian Adrian Liston (32) works as a professor of immunology at the KU Leuven and a researcher at VIB. "I could earn twice as much in the U.S. or Australia, but that is not important."

"I studied at the Australian National University in Canberra and then worked at the University of Washington in Seattle," says Adrian Liston. He received offers from Canada, Australia, Ireland, the United Kingdom and Belgium.

Why come to Belgium?

"Because the VIB is very active in recruiting international researchers. I was looking for a place where I could do research at the highest level. Belgium seemed a pleasant country, with an open attitude towards people who speak English. Belgium also has a good work-life balance".

Do you see differences in the academic environment in Belgium and the U.S.?

"The atmosphere here is more collegial, which is important because academic research requires people to work together. Here the grant system rewards those who make international collaborations. In the United States the grants focus on individual researchers."

"I had the option to earn about twice as much in the U.S. or Australia. The salary of a senior researcher is relatively low in Belgium. But that was not a decisive issue. Most academics are more interested in knowing there is enough money to do the research they are interested in. And in this respect Belgium is doing well."

"There is no crisis in Belgium, unlike the drastic cuts in research funds in America. If an academic was focused on their personal salary they would move to the private sector."

What stops foreign researchers from coming here?

"Academic vacancies aim there focus very specifically on the Belgian market, they are often only internally issued. Universities are less internationally oriented."

"Also the language might scare off some people. At KU Leuven on paper you need to teach in Dutch. In practice you can teach in English, especially at the higher levels, but foreigners do not necessarily know this."

"It would attract a broader set of international researchers if they know they can work in English. Publications, conferences, seminars... it all happens in technical English in our profession."

Are you finally happy with your choice for Belgium?

"Yes, we will stay here for a long time. Belgium is a good place to do research and to raise our son."

This is more-or-less what I actually said. The one point that I think was left out is that Belgium shouldn't be concerned about the "brain drain". In science it is very important to have a "brain circulation", good ideas come from mixing people with different training and backgrounds, so it is actually a great thing for Belgian science if a lot of Belgians leave and non-Belgians come in. Rather than be concerned about the outflow, try to work more on the inflow, and then everyone wins.

Here is the article which started the issue (22% of Belgian researchers leave Belgian, only 18% of researchers came in from abroad, making a small net brain drain). And here is the opposing interview, from a Belgian researcher working in China.

Planning the paediatrics genetics screen

Only fair to have an age-appropriate represenative at the meeting...

Women in Molecular Immunology

It is easy to discuss equality in science through anecodote. Just by spending most of my waking adult life on university campuses across three continents I am fairly confident in saying that sexual equality is better in biology and medicine than in chemistry or physics, is great at undergraduate level and lagging at professorial level, and is better in Australia than in Belgium. Much better than anecodote, though, is quantitative analysis, which is why I love this website. If you don't publish your research it is a hobby, not science, and a good publication record is the A to Z of career success for a scientist. This website collates data on authorship across time and across disciplines, at a global level, and assesses the participation of women. There are a few caveats: papers are only assessed if they are listed in the JSTOR database, and a gender is only assigned by first name analysis (using the US Social Security database as a reference, so it probably fails for first names not commonly used in the US). Still, it is an absolutely beautiful reference point.

There is an wealth of knowledge in this database, but my interest is in molecular immunology, so how are we performing? Well, the question kind of depends on "compared to what?" In 1991-2010, 29.7% of authors on molecular immunology papers were women. This is an improvement from 1971-1990 (23.9%), and a huge improvement from pre-history (being everything from 1970 and before, at 13.7%). It is also outstanding compared to fields such as mathematics, where women still only account for 10% authors (maths clearly has a problem with women; anyone who says the reverse is kidding themselves). But 29.7% is still a long way from 50%. Even among first authors (typically PhD students or post-docs), only 33.2% of molecular immunology authors were women, and among last authors (typically professors) only a dismal 15.4% were women. 

I've said before what I think the problem is (hint, it is men), but this database gives us a resource to see who is fixing the problem, and how fast, and who is content to live in the stone-age and try to do science with a 50% lobotomy. So many questions arise. Why has virology been more equal than immunology throughout the time period? I would love to see a break-down by country to know if this is a discipline-thing, or is a statistical quirk due to regional differences in sexism correlating by chance with regional differences in research focus.

Oh, and for the trivia-minded, within molecular biology the most equal area of research is heat shock proteins, while the most sexist is prostaglandins. In the entire database, the most female-dominated area of research is gender studies (57.8% female authors), while the most male-dominated area of research is a discipline of mathematics called Riemannian manifolds (99.3% male authors). Check it out.

Autoimmune Genetics Laboratory on the front cover of Cellular and Molecular Life Sciences

Our recent analysis of the function of microRNA-29 in the adaptive immune system was features on the front cover of the latest issue of Cellular and Molecular Life Sciences.

Adrian Liston, Aikaterini S Papadopoulou, Dina Danso-Abeam and James Dooley. ‘MicroRNA-29 in the adaptive immune system: setting the threshold’. 2012. Cellular and Molecular Life Sciences. 69(21) p3533. Pubmed | Direct access 

We also did some science

Lab retreat 2012 photos

Aire creates immune tolerance via an unconventional transcriptional mechanism

by Dina Danso-Abeam

The white blood cells of our immune system defend us from infection, a function which is coordinated by T cells. Immature T cells are formed with an ability to attack random targets (an adaptation to the rapid evolution of microbes), which means that by chance some targets are "self-targets" (normal proteins part of a healthy body). As a consequence, these "self-reactive" T cells can atatck the body, so it is critical to prevent them from causing autoimmune disease. To prevent autoimmunity, the immature T cells are screened in an organ called the thymus (located just above the heart), in order to ensure that all self-reactive T cells are eliminated.

The Aire gene plays an important part in eliminating self-raective T cells, by expressing genes that are normally restricted to specific organs (eg, insulin in the pancreas) in the thymus, providing full coverage for screening against self-reactivity. In patients that have mutations in the gene Aire, the thymus cannot provide full coverage of self-targets and fatal autoimmune disease develops. One of the mysteries of how Aire functions is its ability to express thousands of genes like insulin in the thymus. 

It has previously been shown that Aire is a transcription factor (meaning, it can bind DNA to activate genes and cause the expression of proteins) which can activate the expression of other transcription factors. We hypothesized that these secondary transcription factors might mediate the expression of the thousands of Aire-dependent genes like insulin; in effect, we predicted that Aire creates a cascade of transcription factors that results in the expression of thousands of genes.

In order to test this hypothesis, we investigated whether such a cascade regulates the transcription and tolerance of pancreas-specific antigens (e.g. insulin and glucagon) in the thymus. In the pancreas, Pdx1 is the key transcription factor which drives the expression of insulin. Interestingly both Pdx1 and insulin have been shown to be Aire-dependent in the thymus, so it was possible that Pdx1 was acting as a secondary transcription factor in the cascade by which Aire expresses insulin. Therefore we generated mice that specifically lack Pdx1 in the thymus.

By generating these mice, we found that expression of pancreatic-specific antigens such as insulin, needed Aire expression in the thymus, but did not need the transcription factor Pdx1. These results suggest that the broad tolerance that Aire creates in the thymus is not mediated by a conventional cascade of transcription factors, but rather relies on an unconventional transcriptional mechanism.  

This work will be published in a forthcoming issue of The European Journal of Immunology as:

Aire mediates thymic expression and tolerance of pancreatic antigens via an unconventional transcriptional mechanism

by Dina Danso-Abeam, Kim A Staats, Dean Franckaert, Ludo Van Den Bosch, Adrian Liston, Daniel H D Gray* and James Dooley*

If birds are baby dinosaurs and humans are baby apes...

A recent publication in Nature suggests that in many ways, birds are baby dinosaurs. The finding is less unusual than it might seem, afterall it is well established that humans have many traits of baby apes and dogs are in some ways baby wolves. The process is known as paedomorphosis or neoteny - the retention of juvenile traits in the adult form. This can take the form of enlarged eyes (birds), larger brains (humans) or retention of juvenile behaviour (dogs).

The reason why paedomorphosis works is that the basic body plan has much deeper evolutionary roots than the species-specific add-ons. Think of it this way, all mammals pretty much have the genetic program to make a nose, but only the elephant has evolved an additional genetic plan to turn that nose into a trunk. Deep in the genetic code of the elephant there is still the "standard nose" code (and indeed, the foetus has a relatively normal nose), it just has added lines of code that upgrade the standard nose into a trunk. This means that in theory, the elephant could evolve away from the trunk by just ditching the upgrade code, letting it default into the standard nose code. This is true for most of development - new code is never optimally created for the organ, rather it is always adding a bit of extra code to change the outcome. For a software engineer it would be the hight of laziness, creating bloated useless code, with every problem solved by kludge. 

Despite being inefficient and inelegant, the system of "generic code" plus "species specific" is very useful for evolution. This is because species evolve to be adapted to a specific environment. The flamingo beak is fantastic for a filter-feeder, but it has lost the generic functions that a sparrow could use its beak for.

Imagine an island with brine lakes that is populated only by flamingoes. If those brine lakes dried up, the flamingoes would go extinct. But what if new niches opened up? The ordinary "forward" process of evolving a generalist beak is quite slow, because you need to generate new code, but the "backwards" process of paedomorphosis could be quite fast, because it is just the process of deleting the species-specific code, defaulting back to the generic beak (as in anything else, destruction is faster and easier than generation). It is not difficult to imagine a relatively small set of genetic deletions that would mean the adult flamingo retained the juvenile generic beak, and then these "de-evolved" generalist birds could take advantage of the new habitat, and indeed start to evolve specific changes to specialise towards that new habitat.

As a general rule, following a large change in the environment, the generalised (juvenile) body plan is probably going to be more successful than the specialised (adult) body plan. Paedomorphosis in effect provides a default option to revert to in case of catastrophic change, allowing a species to shed its specialised features and start again. One possibility that interests me is that an open niche may drive paedomorphosis by selecting for rapid population growth. Consider the drying up of Africa that occured 5 million years ago. All of the apes that were specialised to live in rainforest would have seen dramatic contraction of their habitat, leaving just a few thousand gorillas left today. But the drying also created a new niche, the savanna, which could be exploited by any ape that was able to adapt. Paedomorphosis probably played a role in human evolution, by shedding the arboreal features required to swing in trees, allowing the pre-humans to venture onto the savana. Now consider the first pre-humans that were suitable for the savana - they has a continent to spread across, with the only limitation being the reproduction rate. We already know that a truly open niche creates an evolutionary pressure to fill it - such as the natural selection of cane toads in Australia with longer legs simply because they can move faster into virgin territory. What if this put selection on humans to reproduce at a younger age? Any variants that became fertile younger (and thus, while still carrying juvenile features) would outcompete the others, creating a population shift. In effect, there would be selection for paedomorphosis simply to increase the reproduction rate, with the retention of other juvenile traits (such as a larger brain) being a side-effect. 

If this model it correct, it would mean that open niches would drive paedomorphosis via two mechanisms - by selecting for the retention of juvenile traits to give a more generalist body plan, and by selecting for sexual maturity at a younger age to give more rapid reproduction. This dual selection force would drive much more rapid evolution, and may be responsible for some of the most remarkable evolutionary shifts, including the evolution of humans. 

AIG laboratory members successful at the FWO

This week we received exciting news that the Autoimmune Genetics laboratory had three successful candidates at the FWO, the premier fellowship program in Belgium. 

Dr Stephanie Humblet-Baron won an FWO Post-doctoral Fellowship award to research a new genetic disease caused by a loss of dendritic cells:

In the immune system, dendritic cells (DCs) are a subset of white blood cells that are specialized to activate lymphocytes when a pathogen is present In the absence of DCs, activation of lymphocytes and clearance of infections is impaired.  A new genetic disease has recently been identified where patients have no DCs, and surprisingly not only do they have poor clearance of infections, but they also have a large expansion of myeloid cells in their blood. For this project we have created a mouse model of this disease, which we will use to try to understand the biology of the myeloid expansion and to test potential therapeutics. 

Dr Susan Schlenner won a Pegasus Post-doctoral Fellowship award to move to the laboratory from Harvard. Here she will use novel genetic approaches to understand the biology of regulatory T cells.

Regulatory T cells are an important subset of white blood cells that have the ability to prevent the immune system from attacking components of the body (“autoimmunity”) and from attacking harmless environmental components (“allergy”). In order to exert this function the regulatory T cells need to be educated as to which components are safe and should be protected from immune attack. The location where this occurs is highly controversial as previously there have not been the correct tools to do functional tests. This project aims to generate a sophisticated set of genetically-altered mouse strains to allow measurement of where regulatory T cells are educated, and then to use these mice in models of autoimmunity and allergy. Having more knowledge about the education process of regulatory T cells may allow the future development of therapeutic interventions in those patients where regulatory T cells fail to prevent autoimmunity or allergy.

Dr Lien Van Eyck won an FWO PhD Fellowship, to move from the clinic to the laboratory to study auto-inflammatory diseases.

Blau Syndrome (BS) and Early Onset Sarcoidosis (EOS) are rare monogenic auto-inflammatory diseases characterized by a clinical triad of granulomatous arthritis, uveitis and rash. Extended manifestations with potentially high morbidity have been reported recently. The pathologic hallmark of BS/EOS is the presence of multinucleated giant cell and epithelioid cell granulomas in affected tissues. Both diseases are associated with gain-of-function mutations in the NOD2 gene. NOD2 is a specialised intracellular protein that plays a critical role in the regulation of the host innate immune response through recognising conserved microbial molecular signatures, thus leading to the induction of pro-inflammatory and anti-microbial responses as well as apoptosis. While the genetic basis of BS/EOS has been characterized, the molecular mechanisms by which NOD2 mutations drive granuloma formation and the development of sarcoidosis remain unclear. A better understanding of these mechanisms is of direct relevance for the development of targeted immunotherapies. The present project aims to determine the mechanisms by which NOD2 gain-of-function mutations lead to immunopathology in BS/EOS by developing a murine model with a gain-of-function mutation in NOD2. This model will allow for a full characterization of the immunopathology of NOD2 associated inflammation, and for the unravelling of molecular and cellular mechanisms involved in disease pathogenesis.