COVID-19 vaccine trial

Today I took part in a COVID-19 vaccine trial (ENSEMBLE2) as a volunteer. It is the Ad26.COV2.S vaccine, an adenovirus-encoded SARS-CoV-2 spike antigen.

Right now, we can use every vaccine we can get. Down the track we can be picky, and use the best ones (if we ever actually find out which are the best! if head-to-head trials aren't done now, they will likely never be done). For now, I'd encourage everyone who is eligible to join a vaccine trial.

As many people possible vaccinated, everyone wearing a mask and eliminate unnecessary contacts. We are so close to beating this virus, every extra death at this stage is an unnecessary trajedy.

Dissecting the immune characteristics of severe COVID-19 responses

• Researchers have analysed immune cell types and numbers from the blood of healthy volunteers, COVID-19 patients experiencing mild-to-moderate effects and patients classified as severe to understand whether particular characteristics of their immune system response can identify treatment targets or indicate disease severity.
• After comparing the T cell immune response, the researchers noted the surprising absence of a strong anti-viral response in the blood of COVID-19 patients.
• The study identified an elevated presence of anti-inflammatory-producing regulatory T cells in the severely affected patients. If confirmed by larger studies, this could be used as a marker for identifying worsening cases and could provide an insight into the mechanism of disease pathology.

A team of immunology experts from Belgium and the UK research organisations have come together to apply their pioneering research methods to put individuals’ COVID-19 response under the microscope. Published today in the journal Clinical and Translational Immunology, their research adds to the developing picture of the immune system response and our understanding of the immunological features associated with the development of severe and life-threatening disease following COVID-19. This understanding is crucial to guide the development of effective healthcare and ‘early-warning’ systems to identify and treat those at risk of a severe response.  

One of the most puzzling questions about the global COVID-19 pandemic is why individuals show such a diverse response. Some people don’t show any symptoms, termed ‘silent spreaders’, whereas some COVID-19 patients require intensive care support as their immune response becomes extreme. Age and underlying health conditions are known to increase the risk of a severe response but the underlying reasons for the hyperactive immune response seen in some individuals is unexplained, although likely to be due to many factors contributing together.

To investigate the immune system variations that might explain the spectrum of responses, teams of researchers from the VIB Centre for Brain and Disease Research and KU Leuven in Belgium and the Babraham Institute in the UK worked with members of the CONTAGIOUS consortium to compare the immune system response to COVID-19 in patients showing mild-moderate or severe effects, using healthy individuals as a control group.

Professor Adrian Liston, senior group leader at the Babraham Institute in the UK, explained: “One of our main motivations for undertaking this research was to understand the complexities of the immune system response occurring in COVID-19 and identify what the hallmarks of severe illness are. We believe that the open sharing of data is key to beating this challenge and so established this data set to allow others to probe and analyse the data independently.”

The researchers specifically looked at the presence of T cells – immune cells with a diverse set of functions depending on their sub-type, with ‘cytotoxic’ T cells able to kill virus-infected cells directly, while other ‘helper’ T cell types modulate the action of other immune cells. The researchers used flow cytometry to separate out the cells of interest from the participants’ blood, based on T cell identification markers, cell activation markers and cytokine cell signalling molecules.

Surprisingly, the T cell response in the blood of COVID-19 patients classified as severe showed few differences from the healthy volunteers. This is in contrast to what would usually be seen after a viral infection, such as the ‘flu. However, the researchers identified an increase in T cells producing a suppressor of cell inflammation called interleukin 10 (IL-10). IL-10 production is a hallmark of activated regulatory T cells present in tissues such as the lungs. While rare in healthy individuals, the researchers were able to detect a large increase in the number of these cells in severe COVID-19 patients.

Potentially, monitoring the level of IL-10 could provide a warning light of disease progression, but the researchers state that larger-scale studies are required to confirm these findings.

“We’ve made progress in identifying the differences between a helpful and a harmful immune response in COVID-19 patients. The way forward requires an expanded study, looking at much larger numbers of patients, and also a longitudinal study, following up patients after illness. This work is already underway, and the data will be available within months,” says Professor Stephanie Humblet-Baron, at the KU Leuven in Belgium.

“This is part of an unprecedented push to understand the immunology of COVID-19”, concludes Professor Liston. “Our understanding of the immunology of this infection has progressed faster than for any other virus in human history – and it is making a real difference in treatment. Clinical strategies, such as switching to dexamethasone, have arisen from a better understanding of the immune pathology of the virus, and survival rates are increasing because of it”.  

Professor Liston and Professor Humblet-Baron both emphasized the importance of the scientific team that led the study. "This work happened during a period of incredible stress. When much of our laboratory was shut down due to the pandemic, Dr Teresa Prezzemolo and Silke Janssens were in the hospital day-after-day, preparing blood samples that were critical not just for this study but for a whole host of clinical trials on COVID-19 based in Leuven. Julika Neumann and Dr Mathijs Willemsen put their PhD research on hold to run samples, and Dr Carlos Roca and Dr Oliver Burton provided the computational support to turn the data into biological understanding. We are both incredibly proud of the entire team."

Neumann, J., Prezzemolo, T., Vanderbeke, L. & Roca, C.P. et al. Increased IL-10-producing regulatory T cells are characteristic of severe cases of COVID-19. Clinical and Translational Immunology

My career feedback strategy

Part of managing staff and students is to manage their scientific progress. Another aspect is to manage their personal growth and career pathway. Often it is easy to forget the latter, so I make sure that at least once a year I have a formal feedback session on management and careers with everyone in my lab. There are five stages to this, and this year it basically took me two weeks (but this is because I am currently still running two fairly large labs, one in Belgium and one in Cambridge).

Step 1: Anonymous survey of the whole lab. Here I use SurveyMonkey, with a series of questions that allow a quantification of satisfaction in different aspects of lab culture. I focus on questions that measure trust and happiness in the lab, like whether people plan to keep in contact with each other after graduation, how well they feel lab duties are balanced, etc. This is useful to get a bird's eye view of lab culture, which is otherwise biased towards the more vocal lab members. It is important not to get hung up on every negative answer - just because 100% of the lab isn't happy in every aspect doesn't mean you are doing things wrong. Instead it should be more of a comparative indicator. Are people more happy with the lab than the institute or vice versa. After a couple of years it also lets you do longitudinal comparisons - are problems being fixed after identification? Here is the list of questions that I used this year, and the answers of my Cambridge lab:

My interpretation: when people's biggest complaints about about seminars and journal club, then you have a healthy lab. We are also fortunate that this year there are many options for online seminar series of very high quality, so alternatives are available.

In the survey I also include a section allowing free-form answers to certain questions. It is more biased (few people answer them all), but also carries more information. This year those free-form questions were:

How should we run lab meeting?

How should we run journal club?

How could lab duties be better assigned, and are there new duties that need to be added?

Long-term, what new skills should we look at developing?

In our science headed in the right direction?

How much productive time did I lose due to COVID?

What new practices, put in place because of the lockdown, should we keep afterwards?

What extra changes should we make for the upcoming six months, to reduce the impact of partial lockdown?

What extra equipment would be nice to have in the lab?

Any other feedback?

Ideally, these would be addressed in the personal feedback (see below), but it is good to have the option for confidential comments.

Step 2: Individual self-evaluation from each lab member. Here I ask everyone to reflect on their strengths and weaknesses, their achievements and ambitions, things that they could have done differently and things that I could have done differently. I generally ask the same questions every year, although this year I had an extra section on how COVID affected them. I make sure to tell people upfront that this is not an official evaluation, it is a self-reflection piece. This is the form I ask them to fill out. This is a really valuable exercise for several reasons:

1) It gives people a time to reflect on their past year and their following year, to contemplate their future career

2) The questions are designed to focus around problem-solving, rather than blame assigning. What can you do to improve your chance of achieving next year's goal? What I can do to help you achieve this goal? Simply getting people to consider their own agency can be the push that is needed to solve problems

3) It let's me know what their goals are, for your next year and your career. The more information I have on where you are going, the more useful my mentoring will be

4) It let's me see how closely aligned their self-evaluation is to my evaluation of them. The biggest management problems arise from unaligned evaluations of skills. If someone is convinced that they are an excellent communicator and you think they are a poor communicator, then that needs to be resolved. Likewise if someone feels like they are behind in their PhD and you think they are ahead of where you expect them to be, that also needs to be resolved. Which brings me to:

Step 3: My written comments on their self-evaluation. Here I go through their evaluation and put down my comments. Where they list their strengths I highlight the ones that I agree with, and I mention strengths that they forgotten. Where they list their weaknesses I comment on weaknesses that I agree need to be fixed, with a proposed strategy, or I'll explain why I don't think the person is actually weak in that aspect, and perhaps it is more an issue of self-confidence than a real weakness. I'll comment on their key achievements, and mention extras that they may have forgotten. I'll discuss their proposed pathways to improvement, oftening higlighting just one for them to focus on in the next year (trying to do everything is not a great approach). I'll reply to where they ask for help, either promising that they will have it, or explaining why that particular suggestion is not suitable and proposing an alternative. I'll comment on their career plans, whether or not I think they are on the right track to achieve them and how they should go about preparing for the next step. I am always honest - I don't see any value in helping a post-doc deceive themselves that they are on the track to independence if they are not - but this does not need to be cruel. It is more about exploring whether or not they actually want to be on that track, explaining what needs to change for them to move onto it, or explaining the alternative track that they may be moving towards without being aware. I make it a point to be positive (especially with people who have under-estimated themselves, a more common phenotype than over-estimation). I also make it a point to recognise where my failings contributed, to take responsibility for this and to commit to a change in myself. Even if that is as simple as "I should have stepped in earlier", it leads by example in taking responsibility for your actions.

I like to give written feedback, even though I'll have a face-to-face meeting afterwards. It gives me the time to organise my thoughts. It lets me read and re-read to see if I struck the right tone. It means I go through all the points on the document. It also lets my staff read and re-read the comments. Sometimes things become emotional in feedback meetings, and your perception of what is being said is changed by the emotional context. You focus in on negatives and forget the positives.

Step 4: A face-to-face meeting. Here there is a follow-up meeting. Usually I don't go through the document - we've both seen the self-evaluation and my comments. I insist on no science at this meeting, it is all about them, our relationship and their career. Often I'll focus on just one aspect that I think is the most important. The meetings usually last thirty minutes, sometimes out to two hours each. Most common themes:

Junior PhD student, learning what a PhD is. Yes, you are on track. You really are. It is normal that you feel like you are not. Of course you don't know everything you need to know, you are here to learn.

Senior PhD student, looking at their next step. Should I stay for a post-doc? Should I write a fellowship? Should I move to industry? You should make a decision based on interest, not based on fear. If you are more interested in industry, go there. Here is how to start building your industry-entry plan. But don't move to industry because you are scared academia is too tough.

Junior post-doc, scared to ask for help. I know you were on top of your game at the end of your PhD, but that doesn't mean you start from the same place in a new lab on a new topic. Science is constantly learning. You need to communicate. If something isn't working, don't hide it until it works. Talk to me. Failure to talk can make our relationship non-functional, and doesn't help anyone.

Senior post-doc, looking at an independent position. Okay, let's look at the facts. How mobile will you be? What are the options available to you and your family? What are the timelines of applications? How early will you need to send me drafts to have sufficient time to address my feedback? Who can I network you with? What do we need to work on with training sessions?

Expecting parent. Alright, let's be realistic here. It is going to be brutal being a new parent. This was my experience. No, you are not going to be able to get X, Y or Z done while on parental leave. Organise everything and we'll get someone else to cover you - but it is up to you to organise things in advance. Samples, folder structure, design of experiments - they need to be able to access everything. When do you get back? Again, let's be realistic and assume you are functioning at 50% productivity for the year after that - anything extra will be a pleasant surprise. Better to finish one thing than leave ten partially completed. Make sure to establish good equal co-parenting from day one!

Super-scientist with crippling self-doubt. You are great, you really are. I know that it is hard to see your success in yourself. I spend half my time in a state of career anxiety, even after a great paper comes out. Sometimes it is just hard to trust your own judgement, and science constantly focuses in on the negatives. If you can't trust your judgement at the moment, trust mine. You're great. 

Step 5. Follow-up! Meetings need actions and behavioural changes to follow. Follow-up with them, make sure that they are putting their actions into place. Follow-up on yourself, check that you are meeting your own commitments. Check-in with them as to whether their goals are changing, especially after big events (that confidence boost from a publication might make them reconsider academia, that tech-transfer conference might have swayed them towards industry). Your relationship with your lab is a work in progress, not a tick-box once a year.

The 2020 Golden Pipette

Congratulations to Julika Neumann for winning the 8th Golden Pipette at the 2020 virtual lab retreat.  

Brutally tough competition this year - the quality of science is just constantly rising year after year. I was really tempted by Orian's UMAP analysis (it looks like an elephant!):

But for that single piece of data that just speaks for itself, it is hard to go past this crystal structure of a point mutation found in a novel primary immunodeficiency gene:

Well done Julika!

Julika receiving the Golden Pipette from past winner Lidia, in our virtual happy hour

Lab retreat 2020 edition

Our lab retreat is a real highlight of the lab, with the Leuven and Cambridge teams getting together to share ideas and progress, brainstorm and socialise. We usually have a couple of retreats a year. Unfortunately our first was cancelled in 2020 by the lockdown, and we decided to make the second one virtual.

Having spent many, many hours on zoom calls over the past six months, I was quite worried about three solid days of a virtual zoom meeting. Fortunately it was a great success! Excellent science (of course) and the level of interaction was as good as an in-person retreat. I don't think it can ever replace in-person meetings, since the success builds on the already-existing personal connections, but perhaps a virtual retreat will substitute for every second retreat going forward?

Secret tips for a zoom retreat:

• Planning in advance. We sent out a spreadsheet with all the links, talk times and titles, discussion blocks, social activities, etc. There was a lot to plan, so I delegated tasks to lots of people, but that still means a lot of follow-up to make sure people have actually done their bit and communicated it. The investment in advance is worth it though! We were lucky to have Dr Loriana Mascali to coordinate much of the retreat, and there was great investment by many lab members on different sections.
• Have a dynamic schedule. Lots of small talks with breaks is easier to handle. For several people we broke up their talk into several subtalks to make sure that all talks were between 10 and 30 minutes. We also arranged to be zoom-bombed by Daisy the goat, to break up the rhythm. Enough discussion time needs to be added, otherwise you'll end up consuming the break time.

• Stick to the schedule as much as possible. Talks that start to really drag on are often those where there are big problems - there is only so long it is helpful to hammer home those points. Build some flexibility into the schedule (so you can keep positive discussions going even if they go over time), but don't let it derail the entire program. Having breakslides is also useful, so that people can always see when the talks resume by looking at the screen, rather than needing to check the program and try to remember if they were five minutes behind or not.
• Actively try to stimulate discussion and interaction. It does not happen organically on zoom, so you need to promote it. I used secret "cheerleaders and shade-throwers". A cheerleader needs to make a positive comment on a talk, while a shade-thrower needs to make a critical comment. They then pass the duty off (in secret) to another person. The net effect is that people get used to making comments, and you have a 2:1 ratio of positive:critical comments. It makes for a lot of conversation and use of the zoom chat. Eventually everyone catches on, but the habit is already established by then! We also used polls, with pre-defined multiple choice questions on each talk. If you see someone not participating, a private chat message can encourage them to engage once, after which they are more likely to engage again.

• Social activities. We had lab bingo running each day (with custom words), which people really got into. Zoom werewolf was a huge success. Virtual escape room was fantastic, which for us was custom made "escape from the lab cold room", but there are plenty of paid options available. Break-out rooms for social interaction are good, but should be broken into smaller groups to get conversation going (6-8 people are good).

• External guests. We invited several potential post-docs / students and long-term collaborators to join. I made it clear up front that they weren't expected for the full three days, and they had the program so that they could jump in for the sessions that interested them the most. A nice way to get expert feedback from people who are not the same old good. 

The ingredients for a successful lab

Trying to reflect on what constitutes a successful lab, these are the 11 ingredients that I work towards bringing together:

A diverse set of experienced staff. Junior staff come in with a passion and enthusiasm that is second to none. However they also are all being trained in the same environment. By contrast post-docs and senior technicians have been trained in different environments, so they bring with them novel experiences. Having a mixture of staff at different levels and with different educational and life backgrounds optimises the chance that the key idea or skill set will be available. Having at least a few staff members with a long-term perspective in the lab is one of the most potent advantages a lab can have - it means the institutional knowledge is shared between multiple staff, and not all residing in the PI.

A dynamic and supportive lab culture. A successful lab is one with high morale, where people see that effort leads to results. The lab culture should be interactive and supportive. A community feeling, where everyone will jump in to get a project over the line, is critical. A place where everyone feels open to speak up and can live with being criticised is a place where experimental design can be optimised before hitting the bench. A healthy lab is one where the PI is only one voice, and there is just as much peer-to-peer flow of information and ideas.

Output spread across the lab. If the output is concentrated in a handful of people it is suggestive of wasted potential, and puts the lab at risk when the productive people move on. Ideally, every researcher should be getting a first author paper every 3 years.

A healthy portfolio of funding. Ideally this includes a mixture of small and large grants, with a long horizon. The reason why I specify a portfolio is that having all of your funding via one large grant creates a difficult problem when that grant is ending.

A pipeline of research projects. A strong research pipeline includes having high potential projects in the incubation stage, development stage, submission/review stage and published. It can be difficult to manage a pipeline, because you need to switch gears between different projects that need different styles of management and cost/benefit analysis. However the advantage is that there is always something cooking, so it doesn't create the problem of synchronised publication and then a long research gap while you start from scratch.

Balance of diversity in research projects. Focus on a topic gives synergy between projects at both the technical and intellectual level. Diversity of topics brings opportunity and reduces risk. Finding the sweet-spot between focus and diversity is difficult but brings advantages.

Creativity and innovation. A successful lab does research that isn't being done somewhere else. This means creativity and innovation, rather than doing the next obvious thing a little faster than the competition. This can come in different forms: developing new tools, to answer questions other people can't, coming up with creative approaches that other groups haven't thought of, or simply asking different questions.

A reserve of soft money. "Soft money", not tied to a project or time-limited, is precious and difficult to obtain. The advantages are enormous though, allowing investments that later lead to grants. A key advantage is that a reserve of soft money can be used to buffer long-term senior staff between grants. Knowing that you can fund senior staff even if there is a year gap between grants helps you keep the most essentially staff in the lab - even if you never need to actually use the reserve

Quality collaborations. A balance between working in isolation and acting as an academic CRO for other labs. Quality collaborations are usually reflected through bidirectional help, where they contribute to your work and you contribute to their work.

Access to high-end equipment and facilities. High level science is increasingly dependent on high level equipment and specialist staff, beyond what can be built and maintained in a single lab.

Supportive institutional and administrative staff. All the ingredients can be there, but if the departmental head is against you or admin work against you, the lab can be crippled. A group leader spending >50% of their time on admin, or research staff spending >25% of their time on admin, is a warning sign.

Congratulations to Julika Neumann!

CCongratulations to the very talented Julika Neumann, who successfully defended her application for a competitive FWO PhD fellowship!

Just starting her PhD, Julika already has several major successes under her belt, including identifying a new primary immunodeficiency (stay tuned!) and spear-heading an open science study on COVID pathology.

We anticipate more great successes from Julika during her FWO fellowship!

The CrispR revolution

Emmanuelle Charpentier and Jennifer Doudna have just won the Nobel Prize for Chemistry. They have been my picks for the prize for years now. Nobel Prizes are often awarded decades after the fact, but CrispR has been such an obvious winner that it is a surprise it took until 2020 to be awarded. (Largely, I guess, due to the politics of several competing claims and patents, that have been going through the courts). 

This Noble is a well-deserved recognition of one of the seminal breakthroughs in biology of the last several decades. The award recognises elegant basic biological experiments that identified a novel immune mechanism that bacteria use to fight off viruses. The key insight is that the chemistry of this system allowed simple modifications to rewire this bacterial system into a tool to edit the genome of essentially any living being. A striking example of blue-skies research on basic science having an incredible translational effect. The CrispR system ranks up there with identifying the structure of DNA or the sequencing of the human genome - indeed, for the first time it allows us to really use the information gained by these earlier revolutions. CrispR tools are used daily across the globe to create new vaccines, generate gene therapy, design bacteria to help industrial processes. Essentially, the discovery of CrispR as a genome-modification tool has put biology on steroids - dramatically accelerating the pace of both basic research and translational applications

Fact-checking COVID-19 claims

From a recent interview with a fact-checking journalist:

Claim: Alcohol-based hand sanitiser shouldn't be used day after day as it breaks down the first immune barrier of the body: the lipid bacteria of the skin.

Verdict: Misleading. Alcohol-based gels do reduce the number of skin-resident bacteria and can start to cause some damage to the skin with prolonged use, in some individuals. However, the skin barrier is irrelevant to COVID-19, and alcohol-based gels also eliminate viruses from the skin, preventing transmission to surfaces and your face. Overall there is a clear benefit to use frequent hand-washing, and the negatives can be countered with moisturising.

Claim: We can strengthen our immune system in weeks or even days (for young people), which would mean that if one does contract COVID-19, it's more likely going to be a mild case which does not require hospitalisation.

Verdict: False. First of all, it is misleading to talk about "strengthening" the immune system. The immune system could be considered more like taste. You can increase how spicy food is, or increase how sweet food is - both are "strengthening" the taste but mean different things. Different "flavours" of the immune response are optimal in different circumstances, so there is no such thing as a generic increase in how strong the immune system is. It is also completely unclear as to whether we actually want a "stronger" immune response in COVID-19 - there is good evidence that an excessive immune response of one particular "flavour" is causing the immune pathology. We want to train the immune response in a particular direction (e.g. through vaccines) not generically increase its power (even if that was possible, which it isn't).

Claim: A well functioning immune system is dependent on the quality of our intestinal flora. This is why we should avoid eating refined "industrial" food.

Verdict: Half true. There is an interaction between the gut bacteria and the immune system, and this is modified by the food we eat. It is not very well understood, and it is likely too early to say whether the net effect of the consequences is generally good or generally bad. It is certainly too early to say whether it makes a positive or negative effect in the case of COVID-19. As general advice, eating fresh and unprocessed foods, high in vegetables and low is red meat is good health advice, regardless of what it does to the immune system.

Claim: Fasting strengthens the immune system in only 3 days.

Verdict: False. Fasting modifies the immune system slightly, which could be advantageous in some circumstances and detrimental in others. It is a minor effect though, and certainly it would not be advised that someone with symptomatic COVID-19 undergoes extensive fasting. The body needs resources to fight an infection.

Claim: Herbal supplements such as echinacea and elderberry strengthen the immune system in a matter of weeks.

Verdict: False. There are active compounds in all plants, which can modify aspects of the immune system if given in high enough doses in a dish. That does not mean that eating a few pills does anything at all. It is very important for people to understand that supplements and medicines are regulated completely differently. "Supplements" are allowed to make essentially any claim, without any evidence, as long as that claim is vague. This is why you get garbage claims about "immune boosting": they are vague enough that they are legally allowed to be made without evidence. Actual medicines, on the other hand, can only make extremely specific claims that are backed up by evidence. All claims about herbal supplements should essentially be treated as advertising material. 

Claim: Vitamins and minerals strengthen the immune system.

Verdict: Misleading. Vitamins and minerals are different from other supplements. They are needed by the body in extremely low quantities, and if they are absent then health problems arise. For people who are actually deficient, taking vitamins and minerals will improve health, including the immune system. However, almost no one in the developed world is actually deficient, and certainly having a balanced diet of fresh food will give you more than enough of every known vitamin and mineral. Unless you have an exceptionally limited diet, taking these tablets doesn't do anything.  

Claim: Fear is a powerful immunodepressant.

Verdict: Half-true. Anxiety can modify the immune system, and can give poorer health outcomes during some types of infection. The effect is weak to moderate, but it is measurable. This should not be used as an excuse not to spread awareness of the COVID-19 pandemic, however: some degree of anxiety is rational and protective, where it supports valid infection-avoidance behaviours (e.g., hand-washing, wearing a mask, avoiding crowded areas).

Claim: Practicing yoga strengthens the immune system.

Verdict: Misleading. There is nothing special about yoga. There are, however, weak to moderate beneficial effects of exercise and the alleviation of anxiety on infection outcomes. For some people, they may get this through yoga. Others may get it through gardening, or a daily run, or the ritual of a cup of tea. We should look after our mental health, which means cultivating habits that make us happy. The idea that one particular solution like yoga or mediation has any special properties beyond this is completely unsupported. Keep it up if you enjoy it, but it doesn't replace medicine and won't work for every person.

Unpopular opinion: the scientific publication system is not the problem

Scientific publishing is undergoing radical change. Nothing surprising there, scientific publishing has been constantly evolving and constantly improving. Innovation and change are needed to improve, although not all innovations end up being useful. I'm on record for saying that the DORA approach, for example, is ideologically well meaning, but so little consideration has been made of the practicalities that the implementation is damaging. Open-access is another example: an excellent ambition, however the pay-to-publish model used for implementation turbo-charged the fake journal industry. I am glad that we have advocates pushing on various reforms to publishing: pre-print, open-access, retractions, innovations in accreditation, pre-registration, replication journals, trials in blind reviewing, publishing reviews, etc. The advocates do seem, to me, to have far too much belief that their particular reform is critical and often turn a blind eye to the potential downsides. That is also okay: the system needs both passionate advocates and dubious skeptics in order to push changes, throw out the ones that don't work and tweak the ones that do work in order to get the best cost/benefit ratio of implementation. Fundamentally, though, the publication system is not broken. Oh, it is certainly flawed and improvements are needed and welcomed. But even if every flaw was fixed (which is probably impossible: some ambitions in publishing are at heart mutually contradictory) I don't think it will have the huge benefits that many advocates assume. Because at the heart of it, the problem is not the publication system, but the other systems that publishing flows into. Let's take two examples:

• Careers. Probably the main reason why flaws in the publishing system drive so much angst is that scientific publication is the main criteria used in awarding positions and grants. So issues with prestige journals, impact factors and so forth have real implications that damage people's lives and destroy careers. DORA is the ambition to not do that, without the solution of an alternative. Perhaps one day we will find a better system (I happen to believe it lies in improving metrics, and valuing a basket of different metrics for different roles, not in pretending metrics don't exist). But even a perfect system (again, probably impossible) won't fix the issue in career anxiety. Because in the end the issue is that the scientific career structure is broken: it is under-funded, built based on short-term perspectives, and operates on the pressure-cooker approach to milking productivity out of people until they break. From a broader perspective, the scientific career structure is not operating in a vacuum - it is part of a capitalist economy which again fuels these anxieties. Why are people so worried about losing their place in the academic pipeline? Because in our economy changing careers is really, really scary. Fixing publishing doesn't actually fix any of those downstream issues.