Self-Doubt: An Anthology of Experiences in the Biomedical Sciences

Introducing our new book, "Self-Doubt: An Anthology of Experiences in the Biomedical Sciences". 

Have you ever had a crisis of self-doubt? A feeling that you are out of your depth and are not cut out for a career in science? I have. At the time I thought it was just me.

After decades of mentoring PhD students and postdocs, I now believe self-doubt is near-ubiquitous, an occupational hazard in science. The hardest part of dealing with your self-doubt believe you are alone in your thoughts. So my lab members and alumni have shared their own stories of career self-doubt.

If you know anyone in science who is doubting their path, please share this book with them (Amazon, Great British Bookshop) so that they know they are not alone

Lung Tregs at the Midwinter Conference

I am very fortunate to be at the Harald von Boehmer Midwinter Conference, courtesy of amazing conference organisers Ludger Klein and Lisa von Boehmer. Highly recommended as one of the best immunology conferences around - I've really been inspired by the great talks in every session. For those of you who would like a taster of the conference, here is my presentation - all unpublished work, covering FlowCode analysis of tissue Tregs, resolving spectral flow cytometry limitations through AutoSpectral, and using a novel AAV-based system of cytokine delivery to the lung to treat Influenza-Associated Pulmonary Aspergillosis. A sneak peak at the work currently going on in the lab! 

Our lab in numbers

We've just had our 200th person join the lab! Welcome to Ida Jobe! I could write books about them as individuals (and have!), but here are our lab members in statistics:

• 38% domestic, 62% international from 54 countries
• 66% women, 33% men, 1% non-binary
• 78% from under-represented groups

New lab photo

Graduation week for Dr Dashwood, Dr Gentry and Dr Ali!

Huge congratulations to Dr Amy Dashwood, Dr Ntombizodwa Gentry and Dr Magda Ali! All three graduating this week with their PhDs from University of Cambridge! Our first Cambridge PhD students, who I find out from reading the acknowledgements were known as "Adrian's Angels" or "The Three Musketeers". Fantastic scientists all, I'm really proud to have been part of their career journey. I look forward to following their successes into the future, already started with a postdoc at the University of Manchester, a postdoc at the MRC Laboratory of Molecular Biology (LMB), and a commercialisation position at Cambridge Enterprise. Well done!

Understanding tissue migration

We have an exciting new bioRxiv story that just went live! This one takes a computational immunology approach to understanding tissue-resident lymphocytes. The story highlights the extra value mathematical modelling can bring to biology.

It starts with a large multi-tissue multi-timepoint parabiosis experiment we ran to understand tissue Tregs. Václav Gergelits, lead author on the study, saw greater potential in this dataset to understand the kinetics of lymphocyte migration broadly.

We extracted turnover data for CD4, CD8, Treg, B cells and NK cells from 17 tissue sources, and generated a sophisticated model of migration, activation and death for each lineage and tissue. The Markov chain modelling found high-confidence solutions that matched the empirical data beautifully.

This tells us a probabilistic model and three distinct states (resting/activated/resident) are sufficient to recapitulate the complex migratory and tissue-residency behaviour of these cells. The cell states change probabilities, but the behaviour is still *probabilistic*.

This means lymphocytes do not have a residency "clock". We can measure the average dwell times for resident cells, but if this average residency time is 3 weeks, it does not mean cells have a 3-week timer. It means the cells have a daily probability of leaving that gives a 3 week average. The dice roll comes up earlier for some cells than for others, within those cells being intrinsically different. Like radioactive decay of atoms, it is just probability - there is nothing intrinsically different about the uranium atoms that decay after a week vs those that decay after a million years, they just had different rolls of the dice.

This approach can explain much of the variation in cell fate without needing to invoke cellular heterogeneity! Two identical cells can have highly divergent outcomes simply because of probability, without different underlying biology. In fact, we can create thousands of identical "digital cells", model them with these simple rules, and we get the empirically-observed range of dwell-times. There is no need to invoke TCR clonality or the like - it is simply an emergent property of cells with probabilistic kinetics!

A great example of applied mathematics informing biology!

Take a read of the pre-print here.

Understanding vaccination in transplant patients

We have a new systems vaccinology paper out at npj Vaccines!

The study tackles the problematic question of why transplant patients responded so poorly to the COVID vaccine. While most people had great antibodies from a single dose, only half of transplant patients have responded even after three!

We took blood from 20 healthy, 31 lung transplant and 59 kidney transplant patients prior to vaccination, and profiled 444 immunological parameters, to get a comprehensive systems immunology profile. We then followed who did and didn't respond to the vaccine, to find the immunological associates.

First up, there are clinical effects: Vaccine response was especially poor soon after transplantation, and in patients on immunosuppressive cocktails, especially those including MMF. Even taking this into account, there were immunological drivers associated with poor response.

As you might predict, the patients that responded best were those with an immune profile that had returned closer to normal post-transplantation. In fact, you could predict vaccine response with 93% accuracy just based on 10 immune parameters.

 

Oddly though, some patients were able to hobble together a poor but detectable response after two shots. These patients didn't have a more normal immune profile, and had quite unusual relationships between immune populations, suggesting that they had put together a poor-but-functional "kludge".

This study was a joint initiative from our lab, Arnaud Marchant's lab at at ULB and Stephanie Humblet-Baron's lab at KU Leuven. 

Huge thanks to all team members, especially Nicolas Gemander, Julika Neumann, Rafael Veiga and Isabelle Etienne for their leadership roles.

Biggest thanks of all to the patients who volunteered for the study!

Read the full paper here

Lab punting

Congratulations Dr Magda Ali!

Congratulations Dr Magda Ali! Our latest successful PhD viva was from the amazing Magda, finishing off a great PhD.

Well done Magda!

Moments before thesis submission...