Faculty position opening up in Leuven

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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.

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*

Thymic involution: how a chance observation saved years of work

An interview with the VIB following the recent publication of our article:

The thymus is an organ crucial for the functioning of our immune system. During aging or infection the thymus can shrink severely, a process called involution. Although the mediators that trigger involution are known, the mechanisms regulating the sensitivity to their presence remained a mystery. Now, Smaragda Papadopoulou from the Bart De Strooper Lab and James Dooley from the Adrian Liston Lab describe in Nature Immunology a microRNA network that plays a key role. A chance observation kick-started the collaboration.

What did you discover about the regulation of thymic involution?

Adrian Liston: The main finding was the tight regulation by miR-29a over sensitivity to thymic involution. miR-29a serves to suppress the involution response, in effect "saving" involution for those situations where we really need it, such as during a major infection. Knowing what drives the reaction of the thymus is important, since it is the only place where T cells can develop. No thymus, no T cells, no infection prevention.

Is there an application side to those results?

For most of us, being born with a healthy thymus, we will generate enough T cells to last a life-time. Thymus involution during an infection is generally not a problem, nor the slow progressive involution that occurs from birth. The major problem is among the very elderly and with radiation/chemotherapy patients. If we could reverse thymic involution in those populations, we could rejuvenate their T cell population, providing them with a younger, more robust, immune system.

How did you go from studying regulatory T-cells to the regulation of thymic involution?

We have been interested in both the thymic epithelium and microRNA for years, so it was natural for us to look at what microRNA does in the thymic epithelium. As for thymic involution in particular, that was observation-driven. When we knocked out microRNA in the thymic epithelium using a Cre-Lox system, the main phenotype was chronic involution. But working out which microRNA is important was an enormous task. The big breakthrough for us was serendipitous. The Bart De Strooper Lab had generated a novel knockout mouse with a defect in one particular microRNA, miR-29a, to look at the neurophenotype. A conversation, a quick look and just by chance this microRNA turned out to be the one we needed for our lead. This enabled us to start a cross-disciplinary collaboration years before anyone else even knew there was a story there.

Did you use or design any new technologies for this research?

Far from it. The most important read-out in this work was the humble cell count. There are still enormous opportunities for high-level research using basic technologies. In this particular case the edge we had was a new mouse strain (the miR-29a knockout) and a new permutation of old mouse strains (Foxn1-Cre and Dicer-flox), but the rest was simply applying old techniques to a new problem. Immunology has so many fascinating questions that remain under-investigated that we spend our time working out which ones to tackle next, rather than designing new technology.

What’s the next step in your microRNA research?

MicroRNA are such interesting molecules. So tiny, they hold only a fraction of the information of a normal gene, yet they are incredibly versatile, affecting multiple completely unrelated targets in every cell type. We pretty much cracked the role of miR-29a in the thymic epithelium, but we are sure it is doing a lot more in other cell types of the immune system.

For the full research results see:

Aikaterini S. Papadopoulou#, James Dooley#*, Michelle A. Linterman, Wim Pierson, Olga Ucar, Bruno Kyewski, Saulius Zuklys, Georg A. Hollander, Patrick Matthys, Daniel H. Gray, Bart De Strooper and Adrian Liston. #Equal first authors. *Co-corresponding authors. 'The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor.' 2012. Nature Immunology. 13 p181.  Pubmed | Direct access

Generation of a family-specific virus through repeated human passage

Generation of a family-specific virus through repeated human passage

Hayden A M Liston¹, Lydia E Makaroff¹ and Adrian Liston ^1,2*
1 Sleepytown University, Brussels 1060, Belgium
² VIB, Leuven 3000, Belgium
*send correspondance to adrian.liston@gmail.com

Nature Junior 8(2) 103-7 

Background. Effective control over viral infection relies on the host carrying appropriate HLA alleles for viral antigen presentation. The explosive expansion of viruses like small-pox into previously isolated human populations demonstrates the potential for certain viral strains to have a disproportionate effect on particular racial groups. As yet, however, a virus with pathogenic potential restricted to the family level has not been identified. Objective. To generate a family-specific virus in an experimental setting, in order to test the feasibility of this occurrence in nature. Methods. A common cold virus was repeatedly passaged between two related individuals for six months. Mechanisms of transmission included frequent kisses, the placement of hands and feet into the mouth and in one instance direct vomiting into the mouth. Results. A single viral strain was propagated with the capacity to chronically infect both members of this family, while having seemingly non-pathological consequences upon exposure to unrelated individuals. The pathogenic loci are predicted to be a dominant HLA carried by both family members, as the experimental inoculation of a third individual, related to one family member but not the other, did not result in pathology. Conclusions. Generation of a family-specific virus is feasible through repeated experimental transfer between family members. A natural situation analogous to the experimental set-up used here would be the transmission that can occur between parents and young children with low levels of personal hygiene. The dominant activity of the HLA cluster in this infection suggests the generation of a regulatory T cell population which inhibits effective immunity against the family-specific virus.

Key Words: virus, horizontal transfer, HLA, human genetics, regulatory T cell.

Balance of the immune system determined by newly discovered T cells

From the VIB Press release: A newly discovered cell type helps to determine the balance of the immune system. The cells are derived from FoxP3(+) regulatory T cells, which recently have been demonstrated to suppress disease during transplantation. Nature Medicine and Blood, two high-ranking scientific journals, are publishing findings by the Autoimmune Genetics Laboratory about this discovery.

 

Innumerable people suffer from immune system disorders. If the immune system is overactive, it can result in allergies and autoimmune diseases such as Systemic lupus erythematosus (SLE). If the immune system is not active enough, infections or tumors occur. It is therefore essential to maintain the right balance.

 

The Autoimmune Genetics Laboratory is investigating a new type of cell that helps to maintain this balance. These ‘follicular regulatory T cells’ (Tfrs) suppress the process by which antibodies are produced during infections and SLE. The Tfrs themselves are daughter cells of FoxP3(+) T cells, key regulators of the immune system.

 

From lupus to cancer

In order to prevent disease the immune system needs to be in balance. If the system is too active, it produces antibodies against harmless substances, as is the case with allergies. An overactive immune system can even attack the body’s own tissues, causing autoimmune diseases such as lupus, rheumatism and diabetes. However, an insufficiently active immune system opens the way for rampant infections and tumors.

 

A complex network of regulatory cells is active to maintain this balance in our bodies. This must ensure that the immune system is sufficiently active and selective so that pathogenic intruders are recognized and eliminated in good time, but at the same time that it does not get out of control. This network of regulatory and activating cells is a long way from being fully unraveled. Dozens of researchers around the world are working to map this network.

 

This Tfr research is a joint collaboration between researchers from VIB-K.U.Leuven, the Australian National University (Aus) and the University of Cambridge (U.K.).

 

Publications

Linterman et al, Foxp3(+) follicular regulatory T cells control the germinal center response, Nat Med, 2011, doi:10.1038/nm.2425

 

Tian et al, Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis, Blood, 2011, doi:10.1182/blood-2011-04-346056

The verdict on Andrew Wakefield: Fraud

In 1998 Andrew Wakefield published a paper which has severely damaged public health in the last ten years. Based on his observations of only twelve children, nine that he claimed had autism, and without a control group, he concluded that the measles/mumps/rubella vaccine caused autism. As a hypothesis, this was fine, unlikely, but not impossible. He saw nine children with autism, reported that their parents linked this onset with the MMR vaccine, and put it in the literature. Why on earth on underpowered observation like this made it into the Lancet is beyond me, but there is nothing wrong with even outlandish hypotheses being published in the scientific literature. Was it a real observation, or just an effect of a small sample size? Was it a causative link, or just due to coincidence in timing?

As with any controversial hypothesis, after this one was published a large number of good scientists went out and tested it. It was tested over and over and over again, and the results are conclusive - there is no link between the MMR vaccine and autism.

In itself, this was of no shame to Andrew Wakefield. Every creative scientist comes up with multiple hypotheses that end up being wrong. People publish hypotheses all the time, then disprove them themselves or have them disproven by others. If you can't admit being wrong, you can't do science, and it is in fact the mark of a good scientist to be able to generate hypotheses that others seek to knock down. Ten of the thirteen authors on the study were able to see the new data and renounce the hypothesis.

The shame to Andrew Wakefield is not that his hypothesis was wrong. No, the shame he has brought upon himself was by being unscientific, unscrupulous and unethical:

1. Firstly, Wakefield did not present his paper as a hypothesis generator, to be tested by independent scientists. Instead he went straight to the media and made the outrageous claim that his paper was evidence that the MMR vaccine should be stopped. This is not the way science or medicine works and was a conclusion unsupported by the data. Worst of all it was a conclusion that many parents without scientific training were tricked into believing. Vaccination rates for MMR went down (autism rates have remained unchanged) and children started dying again of easily preventable childhood diseases. A doctor does not see half a dozen children that developed leukemia after joining a football team and then hold a press conference telling parents that playing sports causes cancer in children, which is the direct equivalent of Wakefield's actions.
2. Secondly, it has now been conclusively demonstrated that his original data was fraudulent. Interviews with the parents of the original nine children with autism show that he faked much of the data of the time of onset, taking cases where autism started before the MMR vaccine and reversing the dates to suggest that the vaccine started the autism. Analysis of the medical records of these children show that as well as the timing being incorrect, many of the symptoms were simply faked and non-existent. The evidence on this charge alone makes Wakefield guilty of professional misconduct and criminal fraud.
3. Thirdly, unknown to the coauthors of the study and the parents of the children, Wakefield had a financial conflict of interest. Before the study had begun, Wakefield had been paid £435 643 to find a link between vaccines and disease as part of a lawsuit. Every scientist must disclose their financial interests in publication so that possible conflicts are known - Wakefield did not. If he had disclosed this to the press conferences the media may have been slightly more skeptical about his outlandish claims.

These last two issues, scientific misconduct and financial conflict of interest, are the reason why the paper was formally retracted by the Lancet. Studies that are wrong don't get retracted, they just get swamped by correct data and gradually forgotten. Instead, the retraction indicates that the Wakefield paper was fradulent and should never have been published in the first place. Likewise, the British General Medical Council investigated the matter and found that Wakefield "failed in his duties as a responsible consultant" and acted "dishonestly and irresponsibly", and thus struck him off the medical registry.

The worst part about this sorry affair is that it is still dampening down vaccination rates. Literally hundreds of studies, with a combined cohort size of a million children, have found no link between the MMR vaccine and autism, yet one fraudulent and retracted study of nine children is still talked about by parents. Some parents are withholding this lifesaving medical treatment from their children, and their good intentions do nothing to mitigate the fact that cases of measles and mumps are now more than 10 times more likely than they were in 1998, and confirmed deaths have resulted. And Andrew Wakefield, the discredited and disbarred doctor who started this all? Making big money in the US by selling fear to worried parents, and deadly disease to children who have no say in it at all.



The historic quandary of antibody production

The mechanism by which antibodies were formed was once one of the oldest and most perplexing mysteries of immunology. The properties of antibody generation, with the capacity of the immune system to generate specific antibodies against any foreign challenge – even artificial compounds which had never previously existed – defied the known laws of genetics.

Three major models of antibody production were proposed before the correct model was derived. The first was the “side-chain” hypothesis put forward by Ehrlich in 1900, in which antibodies were essentially a side-product of a normal cellular process (Ehrlich 1900). Rather than a specific class of proteins, antibodies were just normal cell-surface proteins that bound their antigen merely by chance, and the elevated production in the serum after immunisation was simply due to the bound proteins being released by the cell so that a functional, non-bound, protein could take its place. In this model antibodies “represent nothing more than the side-chains reproduced in excess during regeneration and are therefore pushed off from the protoplasm”.

Figure 1. The “side-chain” hypothesis of antibody formation. Under the side-chain hypothesis, antibodies were normal cell-surface molecules that by chance bound antigens (step 1). The binding of antigen disrupted the normal function of the protein so the antigen-antibody complex was shed (step 2), and the cell responded by replacing the absent protein (step 3). Notably, this model explained the large generation of specific antibodies after immunisation, as surface proteins without specificity would stay bound to the cell surface and not require additional production. The model also allowed a single cell to generate antibodies of multiple specificities.

The “side-chain” model was replaced by the “direct template” hypothesis by Haurowitz in 1930. Under this alternative scenario, antibodies were a distinct class of proteins but with no fixed structure. The antibody-forming cell would take in antigen and use it as a mould on which to cast the structure of the antibody (Breinl and Haurowitz 1930). The resulting fixed-structure protein would then be secreted as an antigen-specific antibody, and the antigen reused to create more antibody. In preference to the “side-chain” hypothesis, the “direct template” hypothesis explained the enormous potential range of antibody specificities and the biochemical similarities between them, but it lacked any mechanism to explain immunological tolerance.

Figure 2. The “direct-template” hypothesis of antibody formation. The direct-template hypothesis postulated that antibodies were a specific class of proteins with highly malleable structure. Antibody-forming cells would take in circulating antigen (step 1) and use this antigen as a mould to modify the structure of antibody (step 2). Upon antibody “setting”, the fixed structure antibody was released into circulation and the antigen cast was reused (step 3). In this model specificity is cast by the antigen, and a single antibody-producing cell can generate multiple different specificities of antibody. 

A third alternative model was put forward by Jerne in 1955 (Jerne 1955). The “natural selection” hypothesis is, in retrospect, quite similar to the “clonal selection” hypothesis, but uses the antibody, rather than the cell, as the unit of selection. In this model the healthy serum contains minute amounts of all possible antibodies. After the exposure to antigen, those antibodies which bind the antigen are taken up phagocytes, and the antibodies are then used as templates to produce more antibodies for production (the reverse of the “direct template” model). As with the “direct template” model, this hypothesis was useful in explaining many aspects of the immune response, but strikingly fails to explain immunological tolerance.

Figure 3. The “natural selection” hypothesis of antibody formation. The theoretical basis of the natural selection hypothesis is the presence in the serum, at undetectable levels, of all possible antibodies, each with a fixed specificity. When antigen is introduced it binds only those antibodies with the correct specificity (step 1), which are then internalised by phagocytes (step 2). These antibodies then act as a template for the production of identical antibodies (step 3), which are secreted (step 4). As with the clonal selection theory, this model postulated fixed specificity antibodies, however it allowed single cells to amplify antibodies of multiple specificities.

When Talmage proposed a revision with more capacity to explain allergy and autoimmunity in 1957 (Talmage 1957), Burnet immediately saw the potential to create an alternative cohesive model, the “clonal selection model” (Burnet 1957). The elegance of the 1957 Burnet model was that by maintaining the basic premise of the Jerne model (that antibody specificity exists prior to antigen exposure) and restricting the production of antibody to at most a few specificities per cell, the unit of selection becomes the cell. Critically, each cell will have “available on its surface representative reactive sites equivalent to those of the globulin they produce” (Burnet 1957). This would then allow only those cells selected by specific antigen exposure to become activated and produce secreted antibody. The advantage of moving from the antibody to the cell as the unit of selection was that concepts of natural selection could then be applied to cells, both allowing immunological tolerance (deletion of particular cells) and specific responsiveness (proliferation of particular cells). As Burnet wrote in his seminal paper, “This is simply a recognition that the expendable cells of the body can be regarded as belonging to clones which have arisen as a result of somatic mutation or conceivably other inheritable change. Each such clone will have some individual characteristic and in a special sense will be subject to an evolutionary process of selective survival within the internal environment of the cell.” (Burnet 1957)

Figure 4. The “clonal selection” hypothesis of antibody formation. Unlike the other models described, the clonal selection model limits each antibody-forming cell to a single antibody specificity, which presents the antibody on the cell surface. Under this scenario, antibody-forming cells that never encounter antigen are simply maintained in the circulation and do not produce secreted antibody (fate 1). By contrast, those cells (or “clones”) which encounter their specific antigen are expanded and start to secrete large amounts of antibody (fate 2). Critically, the clonal selection theory provides a mechanism for immunological tolerance, based on the principle that antibody-producing cells which encounter specific antigen during ontogeny would be eliminated (fate 3).

It is important to note that while the clonal selection theory rapidly gained support as explaining the key features of antibody production, for decades it remained a working model rather than a proven theory. Key support for the model had been generated in 1958 when Nossal and Lederberg demonstrated that each antibody producing cell has a single specificity (Nossal and Lederberg 1958), however a central premise of the model remained pure speculation – the manner by which sufficient diversity in specificity could be generated such that each precursor cell would be unique. “One aspect, however, should be mentioned. The theory requires at some stage in early embryonic development a genetic process for which there is no available precedent. In some way we have to picture a “randomization” of the coding responsible for part of the specification of gamma globulin molecules” (Burnet 1957). Describing the different theories of antibody formation in 1968, ten years after the original hypothesis was put forward, Nossal was careful to add a postscript after his support of the clonal selection hypothesis: “Knowledge in this general area, particularly insights gained from structural analysis, are advancing so rapidly that any statement of view is bound to be out-of-date by the time this book is printed. As this knowledge accumulates, it will favour some theories, but also show up their rough edges. No doubt our idea will seem as primitive to twenty-first century immunologists as Ehrlich’s and Landsteiner’s do today.” (Nossal, 1969).

It was not until the research of Tonegawa, Hood and Leder that the genetic principles of antibody gene rearrangement were discovered (Barstad et al. 1974; Hozumi and Tonegawa 1976; Seidman et al. 1979), rewriting the laws of genetics that one gene encoded one protein, and a mechanism was found for the most fragile of Burnet’s original axioms. The Burnet hypothesis, more than 50 years old and still the central tenant of the adaptive immune system, remains one of the best examples in immunology of the power of a good hypothesis to drive innovative experiments.

References

Barstad et al. (1974). "Mouse immunoglobulin heavy chains are coded by multiple germ line variable region genes." Proc Natl Acad Sci U S A 71(10): 4096-100.

Breinl and Haurowitz (1930). "Chemische Untersuchung des Prazipitates aus Hamoglobin and Anti-Hamoglobin-Serum and Bemerkungen ber die Natur der Antikorper." Z Phyisiol Chem 192: 45-55.

Burnet (1957). "A modification of Jerne's theory of antibody production using the concept of clonal selection." Australian Journal of Science 20: 67-69.

Ehrlich (1900). "On immunity with special reference to cell life." Proc R Soc Lond 66: 424-448.

Hozumi and Tonegawa (1976). "Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions." Proc Natl Acad Sci U S A 73(10): 3628-32.

Jerne (1955). "The Natural-Selection Theory of Antibody Formation." Proc Natl Acad Sci U S A 41(11): 849-57.

Nossal and Lederberg (1958). "Antibody production by single cells." Nature 181(4620): 1419-20.

Nossal (1969). Antibodies and immunity.

Seidman et al. (1979). "A kappa-immunoglobulin gene is formed by site-specific recombination without further somatic mutation." Nature 280(5721): 370-5.

Talmage. (1957). "Allergy and immunology." Annu Rev Med 8: 239-56.

European Research Council funding

A major investment of my time last year and this year was in putting together an application for a European Research Council Start grant. The process was quite an ordeal, with both a substantial written grant and a challenging oral defense, probably consuming over 100 hours of my time. Fortunately, with excellent independent researchers in the laboratory, great research continued to be done in the laboratory while I was locked away with the computer.

Being open to researchers across Europe, in any discipline, the competition is fierce, however there are some large advantages to the ERC Start grant process: 1) the committee looks favourably upon large ideas, rather than safe ideas; 2) the competition is segregated according to career stage, so that I was only competing with other researchers less than five years out from their PhD; 3) the funding is sufficient in scale and duration to really put forward a grand plan. Just recently I found out that the application was approved, and the VIB put out the following press release:

VIB receives high score from European Research Council (ERC)
Two young top researchers awarded €1.5 million research grants!

Leuven - VIB landed two research grants worth 1.5 million euros each. The prestigious grants are courtesy of the European Research Council (ERC) and are aimed at giving talented young scientists the opportunity to develop their own research team. The honor fell to Adrian Liston and Patrik Verstreken, both recently transferred to VIB-K.U.Leuven from abroad.

The European Research Council
ERC was created to encourage excellent research in Europe. ERC starting grants give young talented researchers the opportunity to develop a research group. At present, there are still too few opportunities in Europe for young scientists to initiate and lead their own research, which is extremely unfortunate as it results in top researchers leaving the region to develop their careers elsewhere.

Adrian Liston studies autoimmune diseases.
The immune system is our body's defense system and allows it to fight off foreign substances and micro-organisms. In people with an autoimmune disease, the immune system has gone awry: it can no longer distinguish between the body's own and foreign substances and ends up attacking vital tissues and organs. Adrian Liston studies immune system cells (T cells) that are responsible for this malfunction. With his ERC research grant, he plans to bridge the gap between his research on mice models and humans. This may be a first step in the development of new therapies for autoimmune diseases.

Patrik Verstreken explores the communication between brain cells.
Brain disorders take a major toll on society. Many brain diseases are caused by the disruption of communication between brain cells. Finding a solution depends on understanding this communication in the smallest detail. Patrik Verstreken uses the fruit fly as his model organism for studying genes involved in the communication between brain cells. The ERC research grant gives him the opportunity to expand his research to more complex neural communication networks that control behavior. This step is crucial if we are to understand neurological disorders such as Parkinson's disease.

The inefficient consequences of evolution

Vertebrates are unique in developing an immune system capable of anticipating pathogens that are yet to evolve. Birds and mammals have taken this "adaptive" immune system to the pinnacle, with T cells and B cells using a randomised form of genomic engineering. The advantage of a system based on randomised generation is striking - by making every T cell and B cell unique it becomes exceptionally difficult for pathogens to "out-evolve" their hosts. Regardless of how a pathogen will change, pre-existing T cells and B cells will be capable of recognising the new modified pathogen. The importance of the adaptive immune system to humans is evident in the fatal consequences of its absence, such as patients with end-stage AIDS or primary immunodeficiencies caused by genetic mutations. These benefits greatly outweigh the cost of the adaptive immune system in resources used and the threat of autoimmune disease.

But does the adaptive immune system make vertebrates more healthy? There is no obvious evidence that it does. In a key essay on the topic, Hedrick argues that vertebrates do not appear to have a lower pathogen-induced mortality rate than invertebrates. Instead, he argues that the development of the adaptive immune system provided only a short-term benefit, with pathogens rapidly being specialised to vertebrate hosts. The result is an immunological arms race, with each side incrementally ratcheting up the armaments. Vertebrates are essentially impervious to non-specialised pathogens unless rendered immunodeficient, but the additional mortality from specialised pathogens is probably equivalent to the invertebrate state.

This still-controversial hypothesis high-lights an important aspect of evolution by natural selection. It has highly inefficient consequences. Natural selection takes place at the level of the individual and evolution takes place at the level of the species. Most importantly, natural selection only occurs in the present. An individual who has an advantage for even a single generation will be over-represented in the next generation. A species that has an advantage for a single generation will be able to exploit more resources for reproduction. The long-term consequences - that each species will waste more resources in an ever more expensive battle - is irrelevant.

The evolutionary arms-race between host and pathogen is one incredibly important example. A more illustrative example of the patent futility of this arms-race comes from Sir David Attenborough, one of the leading science communicators of all time. In Life in the Undergrowth, he films two species of harvest ants living in the desert. Each population needs to collect seeds to survive, however the number of seeds produced in the desert is so low that there is fierce inter-species competition. One species of ant is diurnal, the other nocturnal, and each is capable of collecting the entire daily seed dispersal. In order to survive, every second night the nocturnal ants spend an evening carrying rocks to cover the entry hole of the diurnal ants. The diurnal ants can't collect seeds the next day as they need to spend a day clearing the rocks from the entrance. This gives the nocturnal ants a night to harvest the uncollected seeds. The following day the diurnal ants are able to collect every seed and that night the nocturnal ants spend carrying rocks. Two species end up literally carrying rocks backwards and forwards every second day.

The elegance of evolution is the beauty of such specialised behaviour, but the consequences are gross inefficiency in resource use. If each species simply spent alternative cycles conserving resources both species could survive with a higher population density than currently exists. But neither species can be the first to stop the wasteful use of resources, as that would give a fatal advantage to the other, and so they are trapped together in a cycle of carrying stones. The battles of night ants vs day ants and of hosts vs pathogens illustrate the bizarre, elaborate and ofttimes perverse consequences of evolution by natural selection