EXIMIOUS: how does the environment affect our health?

The European funded research project EXIMIOUS sets out to unravel the connections between our immune system and the environment we are exposed to. The Liston lab is proud to be a member of the EXIMIOUS endeavour. 

Each and every day we experience environmental exposures of all kinds, from the air we breathe, the food we eat, the objects we touch, the honking traffic on our way home. Depending on our lifestyle, diet, work and social environments, we all experience a different and complex set of exposures throughout our lifetime. The combination of these, starting as early on as during conception and prenatal phases, during our entire lifetime is defined as the exposome.

The World Health Organisation has drawn attention to the fact that environmental exposures can contribute to the induction, development and progression of immune-mediated, non-communicable diseases, such as autoimmune diseases, allergic diseases and asthma. These are chronic disorders, in which our immune system plays a key role, but for which the underlying causes and prevention strategies are still uncertain. Today, immune-mediated, non-communicable diseases affect about 9% of the European population, with women being two to ten times more likely to suffer from autoimmune diseases than men. If the environment we live in also contributes to these diseases, it is important to know in which way and find a means of prevention.

As of 1 January 2020 the European funded Horizon 2020 research project EXIMIOUS has set out to unravel the connection between the exposome and the immunome (the genes and proteins that make up the immune system), to better understand the role of the environment in immune-mediated diseases. Coordinated by Prof. Peter Hoet from the Katholieke Universiteit Leuven, the 15 EXIMIOUS partners from 7 European countries will collect blood and urine samples from population groups of healthy individuals of different ages, and of patients affected by autoimmune diseases, as well as from population groups with different occupations, such as park workers and miners. This will allow the researchers to build an overview of how different groups of people experience different types of environmental exposures, and how these have an impact on their health. Ultimately, the research efforts of EXIMIOUS aim to provide greater well-being, reduced healthcare costs and improved preventive policies for our society.

“In the EXIMIOUS project, we study how environmental exposures can affect our immune system, possibly leading to a specific immune signature or ‘fingerprints’. We will use these fingerprints as early predictors of immune-mediated diseases,” says Prof. Hoet, who is eager to start working on the EXIMIOUS project with an international and multidisciplinary consortium of experts in immunology, toxicology, clinical medicine, environmental hygiene, epidemiology, bioinformatics and sensor development.

With the ambition and enthusiasm to bring better prevention and help safeguard the health of citizens in Europe and worldwide, the EXIMIOUS team kicked-off the project on 10 February 2020 in Leuven, with representatives of its 15 partners from 7 European countries.

EXIMIOUS is part of the European Human Exposome Network, a joint venture that brings together nine research projects consisting of 126 partners in the largest exposome network worldwide. The EU has committed 106 million euro in funding towards the European Human Exposome Network. On 11 February 2020 in Brussels, EXIMIOUS and its collaborating projects ATHLETE, EPHOR, EQUAL-LIFE, EXPANSE, HEAP, HEDIMED, LONGITOOLS and REMEDIA gave voice to their commitment to work together towards a better and healthier future.

To keep up-to-date on EXIMIOUS’ progress follow @EXIMIOUS_H2020 on Twitter.

About EXIMIOUS The EXIMIOUS project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 874707. It is a five-year Research and Innovation Action (RIA) that officially started in January 2020 and will end in December 2024. It involves fifteen project partners from seven European countries and has a budget of 10.8 million euro.

Immune cell treatment offers hope in tackling neurodegeneration

From the Cambridge Independent

 

Lab activities

  

  

Lab dinner

EU grant success to harness the immune system to treat brain damage

Covered by the BusinessWeekly

Research identifies potential treatment for brain injury and inflammation

Funding awarded to Prof Adrian Liston will be used to advance the approach developed in mice to make it ready for clinical trials. Pioneering research by Prof Liston, a senior group leader at the Babraham Institute, will be developed towards being market-ready for the treatment of brain injury by funding provided by an ERC Proof of Concept grant, as announced today.

Key points:

• Immunology group leader, Prof Adrian Liston, is one of 76 top researchers to receive an ERC Proof of Concept grant, used to translate EU-sponsored research into the clinic.
• Research by Prof Liston's team and collaborators developed a method to use the immune system to prevent brain damage caused by disease and injury.
• EU funding through the European Research Council (ERC) recognises frontier research and provides support to explore the innovation potential of discoveries.
• This funding will also lead the way towards commercialisation and therapeutic application of the technology.

Research undertaken by Prof Liston and his group has shown that driving the expansion of a specific population of immune cells in the brain is effective at treating brain injury in mouse pre-clinical models. The research shows that this approach is effective at treating brain damage caused by disease, such as occurs in mouse models of multiple sclerosis, or injury, such as occurs following a head trauma or stroke.

Professor Liston, senior group leader in the Institute’s Immunology programme, said: “This is an exciting new approach to preventing neurodegenerative diseases. We have been able to come up with a completely new approach to preventing, and potentially reversing, brain damage. At the moment the treatment is proven to work in mice, with the aim to have it ready for transition to human at the end of the year. The immune system is highly conserved between mouse and human, allowing a high degree of success in translation to the clinical. This is illustrated by the immune-based therapeutics developed in mice now successfully being used in the clinic to fight immunological diseases and cancer. This new method may open up a new immune-based strategy to fight neurodegenerative disease”.

The approach harnesses the power of a type of immune cell called regulatory T cells – cells that control the immune response, suppressing the immune system from over-reacting. Increasing the number of these cells in the brain prevents and reverses the inflammatory damage that occurs to the brain during diseases such as mouse models of multiple sclerosis, traumatic brain injury or stroke. The proof-of-concept research demonstrated that just one treatment was sufficient to prevent brain degeneration and stimulate brain repair.

Image: Pre-clinical testing of neuroimmune treatment in mice receiving a brain injury. The mouse on the left was untreated, and developed neurodegeneration. The mouse on the right was treated, with protection from neurodegeneration. Background image uses immunohistology to visualise signs of active brain repair in treated mice. Image credit: Lidia Yshii (VIB, Belgium), Pascal Bielefeld (University of Amsterdam, Netherlands), Sebastian Munck (VIB, Belgium) and Axelle Kerstens (VIB, Belgium).

“It took a multi-disciplinary and international team, spanning both immunology and neuroscience, to come up with a new approach", Prof Liston said. The grant is based on EU-funded research that was performed at the VIB in Belgium and the Babraham Institute in Cambridge. "We have had a talented team pull out all the stops on this, with particular thanks to Dr Lidia Yshii, Dr Emanuela Pasciuto and Dr James Dooley. Key to the success has been collaboration - working with top neuroscientists across Europe, with Prof Matthew Holt from Belgium and Prof Carlos Fitzsimons from the Netherlands providing key insights and skills".

The research grant from the European Union will support the development of this approach over an 18 month period. The funding will allow for the validation of the treatment in pre-clinical trials and the recruitment of a commercial partner for entry into clinical trials in patients.

Professor Michael Wakelam, Institute Director, said: “It’s fantastic that the ERC have recognised the potential of this promising research. Neurodegenerative diseases increase in likelihood and severity with age, so this research very closely aligns with our mission to improve lifelong health. We’re hugely excited to take the next steps towards developing this approach and exploring the wider instances where this type of treatment may offer benefits.”

ERC Proof of Concept grants award €150,000 to researchers to explore the innovation potential of their scientific discoveries and bring the results of their frontier research closer to market.

Unpopular grant review opinions

Unpopular grant review opinion 1. Sections on ethics, equality, open publishing, budgets, etc make grants almost unreadable, and should not be sent to external reviewers.

I am not saying that these things are unimportant - far from it - just that a data dump of 100-page long applications with 10 pages of actual science is not a useful way to do things. Issues such as open publishing and equality could be better dealt with at the institute level. The institute should have the requirement to show they have appropriate policies in place before anyone from that institute can apply. These are not individual researcher issues. Issues such as budgets are best dealt with by financial administrators. Do I know the appropriate budget for a post-doc in Sweden? No. So don't send me 20 pages of financial material. This could, and should, be checked internally and not sent to external review. Guess what, I also don't read Greek. So why are there 15 pages of internal Greek administrative material in the 68-page document sent to me to review? It just makes my life difficult, and makes it more likely I will miss important bits. I'm also not a fan of letters of collaboration. If you say that you work with someone, I'm going to believe you. It is a weird thing to make up. If I can't trust you on that, why trust you on anything you've written?

Too many funding agencies seem like they want to have boxes X, Y and Z ticked, which is good. Unfortunately, rather than actually check it internally they just want a data-dump passed on to reviewers. Reviewers who are selected for their familiarity with the science, not for administrative sections. This approach looks like the boxes are ticked, but it is not actually a good way of effecting change. It sometimes feels more like a protection for the funder, so that they can say it was checked by external reviewers. 

What do I want as a reviewer? First, a simple log-in that doesn't require me to fill in all my details. Then a small application with just the science. I want an easy-to-navigate website, with just two open text boxes (project and applicant) to fill in. I want practical guidelines on what the scores given mean (e.g., funding chance at each score, solid examples of each score). And that's it. Anything more just makes my life harder. 

Unpopular grant review opinion 2. Reviewing grants is an inherently wasteful way to distribute resources.

Yes, grant review filters out some bad ideas and in theory saves money. But science has to fund ideas that won't work. There is no other way to push back the frontiers.

The main alternative is just bulk funding. Block funding every researcher equally is not ideal either. If there are no penalties for failure and no rewards for success, the system can become stagnant. This is why block funding systems were gradually phased out and replace with grant review. But are systems of 100% grant review the most efficient way to allocate resources? An enormous amount of work goes into writing and reviewing good ideas that are never funded. Would it not be preferable to have some of that time spent on science?

I would prefer it if institutes were required to provide a minimum core funding of 2 junior staff or students to each group leader, with appropriate consumables. Yes, this would take up perhaps 50% of research funding. Yes, limits on group leader hiring would be needed. But under this system, the cycle of insecurity and short-termism would be broken. Small labs could work on hard problems over the long-term. Effort would be spent on research not writing unsuccessful grants.

The pot of funding for research grants would be halved in size, but the number of applications would go way down. I suspect that the actual success rate for grants may even rise under this system. A lot of scientists would be okay with a small team, and might even prefer it. At the moment, a lot of applications are made from a place of desperation, for survival of the lab. Group leaders are constantly trying to grow, because often growth or death are the only options. Those "survival" grants would now not be needed. Grant applications would be reserved for either a) those who have proven their ability to efficiently lead a larger team, or b) the small labs that have a special idea that needs the extra boost in resources.

I suspect that this hybrid system would be more efficient than either 100% block funding or 100% grant review funding. Any funders willing to rise to the challenge?

Unpopular grant review opinion 3. Aspirations to remove the use of metrics, such as DORA  are well meaning, but ultimately cause more problems than they solve.

DORA seeks to remove the influence of journal impact factors. For good reason, since impact factors are problematic, and an imperfect measure of quality of the articles in those journals. But do you know what else is imperfect? Every other system.

I am reviewing 12 grants for the same funder. The applicants have an average of 70 papers each. Let's say that a proper deep review of a research paper's quality takes 3 hours. Just the CV assessment would require 2520 hours of deep review. That is nearly 4 months of work. No one actually does that. Even if we had the time, it would be a repeat of effort already done by the peer reviewers at the journal. 

We also need to acknowledge that metrics have strengths. First, they are less amenable to bias then just having one person say the paper is good or bad. Second, they are better at comparing large numbers of applicants - which is the entire point of grant panels. 

DORA principles have their place. In particular, the faculty selection process. But trying to use these principles on grant review panels does not accept the reality of the job that panel members are being asked to do. I would suggest that grant agencies embrace metrics, but do so wisely and cautiously. Develop a useful set of metrics that are given for each applicant. Some off-the-cuff ideas:

• average number of last author papers per lab member per year
• average impact factor of last author papers over the last five years
• average citation number of last author papers from more than five years ago
• average amount of grant funding per impact factor point of last author papers
• number of collaborative papers compared to lab size

I'm not devoted to any of these metrics, but having them would make CV comparison easier and, arguably, fairer. An enormous amount of research should be put into the correct selection of metrics, so that we select for the type of qualities that we want. What you measure is what you get. But the advantages of using metrics are real. We could identify the strengths of the applicant. "This applicant doesn't publish much, but look at the output compared to their funding!" or "Every post-doc who joins this lab ends up with a good paper". Different grant formats could use emphasize different metrics, for example applications for an infrastructure grant should be given a bonus if the applicant has a record of multiple collaborative papers. It just makes sense - they've proven they work with multiple groups. Likewise, post-doc fellowships could be influenced by a metric on their supervisor's success rate with post-docs - I'd rather send a fellow into a lab where most post-docs succeed than to a lab where 90% disappear into the ether. 

There would also need to be a text entry that allows someone to make a case that the metrics are not appropriate in their particular case. I am happy to look beyond metrics if the applicant can convince me there is a reason to. But that should be the case for the applicant to make, rather than throwing out all of the quantifiable meta-data. Blindly using one metric is bad, but intelligently using multiple metrics, tailored to the purpose of the grant, just makes sense. 

Conclusion. We could be doing grant review much better. Right now, I am not even sure that we are moving in the right direction. I'd like to see more involvement from grant agencies, and a more thoughtful assessment of the burden of peer review on both applicant and reviewer. Scientists should just be reviewing the science, and we should be given useful tools to do so. Administrative issues should be audited independently, and often at the level of the institute rather than the grant. These are complex issues, and on another day I might even argue the opposite case for each opinion above, but the important thing is that we should be having a fearless and data-led discussion on the topic. 

New lab babies!

Congratulations to Dr Kailash Singh and Dr Emanuela Pasciuto, who both had new babies in the past weeks. Lab babies number 12 and 13, respectively!

Lafferty debate, ASI

One of my favourite events of the scientific year, the humorous Lafferty debate at ASI 2019. 

This year, the value of mouse research. Fantastic points put forward on the incredible value that mouse research has given to immunology. Right now it is popular to diss mouse work, but it is worth remembering that almost the entire basis of immunology - the cell types, the immune responses, the origin of immune diseases - is based on mouse immunology. Yes, there are some differences between mouse and human, but the incredible advances in treating immunological diseases have come from work that developed in mouse. Parallel mouse-human research is the only method that has actually cured disease, so let's not throw out the winning formula.

Congratulations Dr Erika Van Nieuwenhove!

A huge round of congratulations for Dr Erika Van Nieuwenhove, who successfully defended her PhD. Erika set for gold standard for PhD defences, with an outstanding presentation and masterful question time. Erika's thesis was on inborn errors of immunity, with her PhD covering multiple new genetic mechanisms for PIDs, including mutations in ADA2 and Ikaros, plus a machine learning-driven approach to the diagnosis of JIA. The work is not yet finished either - stayed tuned for more Van Nieuwenhove papers on new genetic causes of neutropenia! A future leader in pediatric immunology and rheumatology!

Interview with Louisa Wood

 Where were you and what were you doing before you joined the Institute?

I was a professor at the University of Leuven and VIB, in Belgium. I set up my lab there in 2009, and spent the last 10 years growing a research program and setting up two core facilities. 

What has the relocation experience been like so far? Best bit and worse bit?

I might plead the fifth there! Problems are for solving, not complaining about. 

What’s your research about?

I've always admired scientists who chose one problem and spend a career on solving it at a deeper and deeper level, but that isn't my personality. I love the creative process, hearing about a problem and them coming up with a spark, a creative way to tackle that problem. It has been a fun way for me to work, and we've made major contributions in different fields - basic immunology, clinical immunology, endocrinology, microbiology, neuroscience, genetics, bioinformatics - but I've generally avoiding asking the follow-up questions. I think as my career has matured, I might be ready to settle down with that one special question through: what is the adaptive immune system doing in the tissues? 

Any advice from what you’ve learned from setting up your own lab?

There are different routes to success, and you need to find one that works for you. From my perspective, the key to my success (survival? I guess they mean a similar thing in academia) has been rapidly building a diverse portfolio. Key here was my first hire - James Dooley (still with me 10 years later, having relocated over to the Babraham with me). He came on as an experienced research assistant from a small lab (an amazing training ground, since techs in small labs are expected to know how to do everything). Having someone that I could trust in the lab let me write grants. I wrote and wrote and wrote - I brought in 22 grants and 19 fellowships over my 10 years in Belgium, and must have submitted one a month on average. The whole time I saw James develop as a lab manager and then a senior scientist, and saw that he was actually much better in the lab than I ever would be, so the relationship turned into a partnership, with each of us taking the lead in our area of expertise. So I guess the key advice would be to hire James - but he already has a job, so hands off! Seriously though, hire the best, give them your trust and support, and let them take on responsibilities as they grow. It means making a serious commitment to their careers: senior staff grow more valuable every year, and this should be reflected in their salary and job stability.  

Do  you  have  any  words  of  wisdom  for  those  starting  off  in  a  scientific career? What do you know now that you wish you’d known then?

First, attitude matters when you hire someone. Unfortunately, not everyone is in science because they care about it. I've had people with very competent CVs join my lab for the wrong reason, like wanting to get a PhD. Ultimately, if you don't really care about the science, you won't be a good scientist. Skills can be taught, but I've never found a good way to mentor someone who didn't have a positive attitude, so my advice to a younger me would be: when you see those warning signs, give that person their notice. Attitude also matters in the other direction: when we needed to hire a mouse technician we passed over people with experience to take on Jeason Haughton, a Jamaican life guard with no experience in science at all. Why? Because we could tell that he was ready to listen, ready to learn and ready to work. Jeason has now been with me for 6 years, and there was a long line-up from other labs desperate to take him on when I moved over to Cambridge!

Second, peer review is over-rated. There is a degree of "reviewer roulette" at play that you can't take too personally. Great grants get rejected all the time. My first small grant to a Belgian funder was rejected - a few months later I submitted more-or-less the same thing to the ERC and gained a €1.5m grant that led to great papers. Papers will get rejected at one journal, and then accepted at a better journal. Why? Reviewer roulette. Oh, there have certainly been occasions when a reviewer's suggestions improved a paper, but more often it is just extra stuff for the supplementary material. My advice is to accept it is a game, and win through numbers. Why invest all your emotional energy into one grant, when you can write four or five? If a paper is rejected from one journal, resubmit to the next that day. Start juggling with as many balls as you can competently handle (the trick is working out how many that is), and make sure they are always in motion. 

Who has inspired you? Why?

David Attenborough. From the youngest age, watching his documentaries guided me into thinking like a scientist. To try to understand life through the prism of evolution, to understand living systems as complex positive and negative feedback loops. I still find that I bring a very ecological style of thinking to understanding immunology. He also shaped by ethics and my politics - because of him, I am a lifelong vegetarian and ardent environmentalist. For an inspiration from an immunologist, I've also admired the work of Gitta Stockinger (now at the Crick). Someone who is prepared to do a deep-dive into a question, and not just crop off the easy big hits: her work on Th17 cells and the aryl hyrdocarbon receptor are some of the best reads in the field. I'd also add: I think it is important to tell people how much you admire them! Science is a tough business, and even the most senior people deserve positive affirmation. I had the pleasure of successfully nominating Gitta for an EFIS-IL award in 2017, and it was a pleasure to introduce her award plenary and describe her to everyone as one of my scientific heroes. Just recently I sent a letter to Sir David, thanking him for his influence (and received a nice reply too). 

What has been your proudest personal and/or scientific achievement?

Here I would bring up two post-doctoral fellows who joined my lab back in Belgium - Stephanie Humblet-Baron (joined 2010, as her first post-doc) and Susan Schlenner (joined 2012, as her second post-doc). Both are amazing scientists, Stephanie as a clinical/translational immunologist and Susan as a molecular immunologist, who took on slow-burning projects. For Stephanie, it was six years between her starting in my lab and getting her first paper - but since then a big hit every year! Susan not only started ambitious projects but also set up a CrispR facility at the University of Leuven - a job that has helped many labs, but is not exactly a career builder. In both of them I saw future leaders. They were already at an amazing level scientifically, so my mentorship was to help build their understanding of how a lab works, strategies for writing grants and papers, discussions on how to manage staff, advice on how to build and maintain a portfolio of projects, and guidance through the tenure-track application process. So among my proudest scientific moments were when they were both made tenure-track professors at the University of Leuven - Susan in 2017 and Stephanie in 2019. Two outstanding scientists from my lab who are now independent. I don't think I could have left Belgium without knowing that my lab and Core facilities there would continue to flourish, now under their leadership.