Well done to Dr Ana Acosta, who successfully defended her PhD today! Ana tackled a challenging and exciting project on the role of HNF1A in monogenic diabetes, generating a new mouse model and validating results in primary human islets. Her work dramatically alters the way we see HNF1A in glucose homeostasis and diabetes. A very productive PhD, performed at University of Lille, with Prof Caroline Bonner, and the University of Leuven, with my team. The 20th PhD student to graduate from my lab, and one of the last from our Leuven days! Great job Dr Acosta!
Our lab has a new study on primary immunodeficiencies out now at Cellular & Molecular Biology! We studied two families with combined immunodeficiency and found mutations in the Calcium channel ITPR3. The mutations reduce the function of the channel, making the channels 100-fold less capable of initiating a Calcium flux after cellular stimulation. T cells from the patient had poor responses throughout the signalling cascade: reduced Calcium flux, poor nuclear localisation of NFAT1 and reduced proliferative burst, explaining the impeded response to infections. The most severe patient required a bone-marrow transplantation to correct the defect, while the other patient is doing well with regular IgIV treatment. The work established ITPR3 as a new cause of primary immunodeficiency, after previously assuming that these Calcium channels had too much redundancy to be a cause of genetic disease. Read the full paper here, or take a look at the illustrated abstract below for a short-cut summary!
Exciting new paper out from the lab on using gene delivery to protect against diabetes. The work is based on the "fragile beta cell" hypothesis, which postulates that some individuals are prone to diabetes because their beta cells are more prone to fail during stress situations. We previously demonstrated that the Glis3-Manf axis was central to dictacting how robust or fragile beta cells were, during stresses either immunological (type 1 diabetes) or metabolic (type 2 diabetes) in origin. Based on this data, we designed a gene delivery system, which essentially tricks beta cells into making more Manf and becomes robust in the face of stress. NOD mice, treated with this gene delivery of Manf, become resistant to diabetes. As the gene delivery system we use harnesses the endogenous insulin promoter (specific to beta cells, and upregulated during cellular stress), we can use low doses of the gene delivery system delivered intravenously, without altering the rest of the body. This gives the system a high potential for clinical translation. Read the full paper here, or check out our illustrated abstract below.
One of the biggest challenges of having your own team as a PI is learning how to communicate with them about behaviour you are unhappy with. For me, this is often about deadlines. I hate deadlines being missed, and in particular I hate it when a deadline is missed and not communicatd, and basically it is on me to realise, chase up with the person, diagnose the problem and arrange a new deadline. Because it annoys me so much, I go out of my way to make the deadlines achievable - I ask my team member how long they think a task will take, and then I'll often add on a few days or weeks if I think they are under-estimating it (or if the deadline would fall during a period where I wouldn't be able to respond anyway). I'm also highly receptive to a team member telling me, in advance, "I know that we agreed on X as a deadline, but I can already tell I won't make that, can we push the deadline back to Y". With all that being the case, some people repeatedly miss deadlines, and it really grinds my geers. It is one of the easiest ways to sour a professional relationship with me (which, incidently, I explicitly write in my "lab policies" doc that I give to new lab members - it is not a secret!). If it is frustrating me, then I need to bring up the issue with my team member and deal with it. Here is my secret:Use "I language". To explain "I language", it is easiest to start with "you language". "You language" is saying "you missed this deadline". The problem with this is that it immediately puts the person on the defensive: you'll see them coming up with excuses or rationalisations. That isn't a productive mindset for you to change someone's behaviour."I language" reframes the debate. "I feel really disrespected that you missed this deadline and gave the work to me late. I had reserved Friday morning to work on it, but instead I had to skip out on going to the park with my son on Saturday because I got this late. I know that this feels like a one-off to you, but when I manage a team of 15, people only need to do this twice a year to ruin almost every weekend for me. This is really important to me, and now that this has happened several times I feel like you don't respect me or value my time".Advantages of "I language":
it is actually true. The problem that you are addressing isn't actually their action. The real problem is that this particular action hurts you. We all have different trigger points - messy bench, missed deadlines, swearing, having the radio on - each of these will cause one person to grind their teeth while another person literally won't notice. How do they know this is a sensitive issue for you without you telling them?
it emphasizes the importance of the issue. For some people, deadlines just aren't that important, so it is hard to make them feel like deadlines are important to them. But they can understand that missing weekend after weekend with your child is important to you, and once you link the two they will get it
it puts the other person in a zone of empathy rather than in a zone of defence. They don't feel attacked, they feel taken into your confidence, and are gaining an insight into what is important to you
word spreads faster. People don't like to share that they got told off, but they will share that you are really sensitive to some particular things
it works. Except for sociopaths, people don't like causing pain to other people. If you find that "you language" works better on someone than "I language", that is a giant red flag that that person has no empathy or ability to work as a team
This probably sounds a lot more like relationship advice than mentoring advice. Which is because it is - I got it from "Why Marriages Succeed or Fail", a scientific analysis of relationships based on recording and analysing real interactions between couples and then correlating these interactions with later divorce rates. While the book is about personal relationships, I believe that the data holds just as true for professional relationships. It is well worth a read for other tips, such as making sure you have a good ratio between positive and negative feedback.
Source of immune signals alters the immune response
Key points:
Researchers have identified source-specific effects of the signalling molecule interleukin 2 (IL2) on the immune response.
IL2 is an important signalling molecule that has been harnessed as a biologic therapy for a number of diseases but can result in unwanted side-effects.
This study, conducted using new mouse models, found that the immune response to IL2 is dependent on the cellular source of the IL2 production.
Their new insight explains the link between IL2 treatments and side-effects, opening up the potential to apply this powerful immune modulator to optimise treatments while avoiding off-target effects.
A detailed update to our understanding of the key immune system signalling molecule interleukin 2 has been published today by researchers at the Babraham Institute. Their findings explain common side effects of IL2-based therapies, and identify potential new uses of IL2 as an immune-modulating biologic drug. This research was only possible thanks to a new mouse model which allowed researchers to control which immune cell types produced IL2. With further research, this understanding of the rules dictating which cells respond to IL2 could allow scientists to optimise autoimmune and cancer treatment while avoiding unwanted side-effects.
Dr Carly Whyte, lead author on the paper who undertook this research as a postdoctoral researcher in the Liston lab, said: "IL2 is a protein that is normally tightly regulated in the immune system because it has such strong effects. However, when IL2 is given as a therapeutic treatment, these normal restrictions on IL2 are overruled. By using mouse models, we have found that the presence of IL2 in certain zones of the immune system leads to some of the same side-effects that we see in human patients treated with IL2. We hope that by understanding more about how IL2 works in different zones, this treatment might be tailored to be more effective."
IL2 is involved in a large number of different communication networks in the immune system, being produced by a variety of cellular sources and affecting a diversity of cell ‘responders’. It is not only needed for maintaining regulatory T cells, which prevent our body’s immune system from attacking itself, but also CD8 T cells, which attack tumour cells and virus-infected cells. Owing to this dual functionality, IL2 has been harnessed to both promote an immune response, and limit one, depending on the target cells. Despite being actively explored in hundreds of ongoing clinical trials, the full therapeutic potential is currently limited by frequently-encountered side-effects.
Previous explanations for these side-effects were based on the high doses of IL2 when given as a biologic drug, but Prof. Adrian Liston and his team were able to demonstrate that the cell-type making IL2, and the location of those cells, dramatically change the consequences of IL2 exposure. Dr Kailash Singh, co-lead author, explains "Our genetically modified mouse models showed that the immune responses are varied depending on the source of IL2. Our findings revealed that the IL2 response is very much context-dependent, and is not solely due to the concentration of IL2."
Prof. Liston, a senior group leader in the Institute’s Immunology research programme, said: “This work changes the way we think about IL2 as a decades-old therapeutic molecule, demonstrating that it is not just the dose of the IL2 that matters, but also where it is located in the body. Putting together the pieces of this cause and effect intricacy has involved several remarkable scientists and over a decade of research. It was only by bringing together experts in animal research, flow cytometry and immunology, that we had the know-how to tackle the complexity of this question. We’re increasingly aware of the therapeutic power of the immune system, and these findings provide a new avenue of investigation for designing biologic drugs.”
Dr James Dooley, joint senior author of the study, said: "The next generation of biologics will be smarter and tailored to the biology of the disease. This work teaches us that one route of smart design of IL2 is to target delivery to different parts of the body, potentially allowing us to drive very different therapeutic outcomes in patients."
Wednesday, November 9, 2022 at 11:56AM 
