Success and failure in science

Science is a very competitive field and demands a high level of success. Not only do you need to make an advance, but you need to make a major advance, get it published in a top-tier journal and repeat over and over again to have a career in the field.

But perhaps how science treats failure is the really remarkable part. Science is remarkably tolerant of failure, even repeated failure. I've probably had 500 rejections from scientific journals - I don't even bother counting. My grant rejection rate is over 50%. I've had projects that have been cut after years of investment, with no return. It happens, and you get used to it.

As scientists we are always inching our way forward into the unknown, making wrong turn after wrong turn until we finally stumble onto a new truth. Constant, gruelling failure is just built into the system. This is one of the toughest lessons for new PhD students to learn - yes, nothing is working, but that is normal! My first paper was one of the most important of my career, earning me my post-doc position and being critical for my faculty position. Yet if you were to look at all the experiments that are included in the paper, they probably only took an accumulated 10 days. The actual project took two years, but most of that time was design, breeding and genotyping, experimental troubleshooting, and generally being busy without producing results.

It is a funny thing to consider, but science completely ignores all of your failures and judges you on your absolutely best days. Those few days that get results are the ones that make your paper. Even if you have published a hundred papers, you are only judged on the best five. So to students that are stressed out about failure - don't worry, failure is normal and healthy in science, and will never be held against you. If you can follow up four years of failure with one good breakthrough, you will be widely congratulated and rewarded.

Shaping the human immune system

In the current issue of Trends in Immunology, we synthesize the latest literature on "population immunology", on the nature of variation in the immune system and our current understanding of the relevant drivers. 

Read: Liston, Carr and Linterman (2016). "Shaping variation in the human immune system". Trends in Immunology. 

Niet genen bepalen immuunsysteem maar omgeving

De Morgan, Sara Vandekerckhove 30-Sept, pg13

Iedereen heeft een uniek immuunsysteem. Maar hoe die 'witte soldaten' er uitzien, hangt grotendeels af van onze omgeving en niet van onze genen. Belgische onderzoekers proberen nu de hele immuuncode te ontrafelen.

"We stappen steeds meer af van het simplistische idee dat er slechts één type immuunsysteem bestaat", zegt Adrian Liston, hoofd van het VIB-KU Leuven Laboratorium voor Translationele Immunologie. Samen met twee andere immunologen gaf ze in een review in Trends in Immunology haar visie op de nieuwe inzichten erover.

Elke mens erft een uniek genenpakket dat ons helpt om infecties te overwinnen en dat bepaalt hoe ons immuunsysteem eruitziet. Maar recent onderzoek heeft nu uitgewezen dat niet die genen, maar onze geschiedenis, omgeving en levensstijl voor 60 tot 80 procent verantwoordelijk zijn voor de verschillen tussen immuunsystemen.

Drie belangrijke factoren bepalen mee hoe goed of slecht je reageert op allerlei bacteriën en virussen.

1. Infecties

De meeste verschillen tussen mensen als het over het immuunsysteem gaat, zijn te wijten aan langdurige infecties. Loopt iemand herpes of gordelroos op, dan heeft dat een enorm effect op de 'witte soldaten'. De wisselwerking tussen het virus en het immuunsysteem verandert langzaam de cellulaire samenstelling ervan en maakt het meteen ook gevoeliger voor dat specifieke virus.

Bovendien maakt het je meteen ook vatbaarder voor allerlei andere virussen. Bij mensen die niet geïnfecteerd raken, vinden die veranderingen niet plaats. Hun immuunsysteem blijft door de jaren heen relatief stabiel.

2. Leeftijd

Vanaf een bepaalde leeftijd slaat het immuunsysteem weer 'op hol'. Leeftijd speelt een belangrijke rol in de evolutie ervan. Waarom precies hebben onderzoekers nog niet kunnen achterhalen, maar het is wel bewezen dat het immuunsysteem anders reageert op bedreigingen van buitenaf naarmate we ouder worden.

Dat heef te maken met de thymus of zwezerik, een orgaan dat verschrompelt na de puberteit, en vervolgens geen cellen meer produceert die net infecties helpen bestrijden. Eens de thymus het laat afweten, word je sneller ziek.

3. Omgeving en levensstijl

Onderzoek bij mensen die samenleven heeft aangetoond dat de omgeving en de levensstijl een groot effect hebben op de levensstijl. Luchtkwaliteit, voeding, stress, slaappatronen hebben een grote impact op hoe goed je gewapend bent tegen virussen en bacteriën. Koppels die samenwonen hebben een gelijkaardig immuunsysteem.

Where You Live Shapes Your Immune System More than Your Genes

Cell Press press-release:

Like fingerprints, immune systems vary from person to person. And while we all inherit a unique set of T cells and B cells from our parents, recent studies have found that our environment—like where and with whom we live—is responsible for 60% to 80% of the differences between individual immune systems, while genetics account for the rest. In a Review published September 29 in Trends in Immunology, three immunologists discuss the emerging science of what shapes our immune systems and how it might be applied.

“Just like it took a while to crack the genetic code, we’re finally starting to crack the immune code, and we’re shifting away from the simplistic idea that there is only one type of immune system,” says lead author Adrian Liston, head of the VIB Translational Immunology Laboratory in Belgium. “Diversity isn’t just programmed into our genes-- it’s programmed into how our genes respond to the environment.”

Long-term infections are responsible for most of the differences between individual immune systems. For example, when a person has herpes or shingles, the virus has more opportunities to interact with the immune system. These interactions slowly change the cellular make-up of their immune system and make it more sensitive to that specific virus, but also easier for other infections to slip past its defenses. People without these infections don’t experience these cellular changes, and even with the occasional cold or fever, their immune systems stay relatively stable.

The exception is when a person is elderly. Researchers haven’t determined exactly why age plays a major role in making our individual immune systems more unique, but they have shown that aging changes how our immune system responds to threats. As we get older, an organ called the thymus gradually stops producing T cells, which are made to help to fight off infection. Without new T cells, older people are more likely to get sick and less likely to respond to vaccines.

“A lot of diseases that we associated with aging have an inflammatory component, which suggests there is likely immune involvement,” says Michelle Linterman, a researcher at the Babraham Institute and co-author of the review. “Understanding how the immune system changes with age is going to be hugely important for treating age-related diseases in the future.”

 Differences can be overcome, however; studies of people living together have shown that air quality, food, stress levels, sleep patterns, and lifestyle choices had a strong combined effect on our immune responses. For example, couples who cohabitate have more similar immune systems compared to the general public.

Liston and his collaborators, Linterman and Edward Carr of the Babraham Institute, would next like to explore how changing our environment could purposefully shape our immune system and potentially affect our health. “In order to tinker with the immune code, we first need to really understand the influences that shape the immune system,” says Liston. “That’s why it’s actually great that environment is more important than genetics, because we can play with environment.”

Read: Liston, Carr and Linterman (2016). "Shaping variation in the human immune system". Trends in Immunology. 

Understanding variation in the human immune system

My talk from the recent Eppendorf Young Investigator Award ceremony on variation in the human immune system.

Journal club: Genetics breaks the relationship between obesity and diabetes

Samoans tend to be physically large people, with a very strong build in addition to being at high risk for obesity. More than 50% of Samoans are obese, one of the highest rates in the world. A recent paper in Nature Genetics mapped this susceptibility to obesity to a mutation in CREBRF (p.Arg475Gln), which is common in Samoans and very rare in the rest of the world. This gene is extremely potent, the strongest obesity-causing polymorphism yet found.

Samoans also have one of the highest rates of type 2 diabetes in the world, so it is very easy to point a finger and assume that CREBRF causes both obesity and diabetes. Intruigingly, this is wrong - CREBRF (p.Arg475Gln) drives obesity but actually protects against diabetes! 

Increasingly, the theoretical correlation between BMI and diabetes seems to be breaking down. China is having both an obesity and diabetes epidemic, with the transition to a Western diet, but in China there is essentially no correlation between BMI and diabetes. It is starting to look as if diet drives these two phenomenons independently, and diabetes is not simply a consequence of obesity.

Read the article: Minster, R.L. et al. 'A thrifty variant in CREBRF strongly influences body mass index in Samoans'. Nature Genetics 48, 1049–1054 (2016).

Inbreeding in Flemish academia?

A newly released study of Flemish PhD graduates has found that fully 20% of Flemish PhD graduates go on to get a professorship in a Flemish university. This compares to perhaps 2% of American PhD graduates, so great news for the Flemish system, right?

I would argue the (unpopular) position that this is too high a rate of PhD to professorship transition. This is not to say that good PhD students shouldn't be given good jobs - just that most should find their niche outside academia. In my experience in the Flemish system, I would say perhaps half of PhD students really shine during their PhD (the system does not formally differentiate, but there are "good PhDs" and "average PhDs"). Many of these stars have talents that are not especially well aligned with remaining in academia - perhaps they are more interested in industry, law, journalism or the myriad of other jobs that a PhD is great training for. So the 20% figure is, to me, far to high. A 5-10% figure would be a good success rate based on my experience.

The other pertinent question is whether this system, with such a high success rate, produces the best outcome for Flemish science. Currently, 97% of all professors obtained their PhD in Belgium, and 75% even obtained their PhD at the same university! These are astronomical figures, especially for a tiny country with close neighbours that are also producing amazing PhD students. These numbers are not based on ancient history either, they are from the 2010 professorship appointments. 

My point is not that Flemish universities are producing sub-par PhD students that should be replaced by foreigners. Far from it - we are producing some outstanding PhDs that should be snapped up for prime positions around the world! My point is instead that an institution that is based almost entirely on internal hiring is going to have severe intellectual inbreeding. One great unique thinker is worth a fortune - clone them a 100-fold and have them work together and you get diminishing returns. It also shuts out the brain circulation that you get when externally recruiting. I'd love to see a hundred Flemish PhDs go out into the world and spread their exciting ideas, and (simultaneously) a hundred foreign PhDs come in and bring their exciting ideas with them. It can happen for people who post-doc abroad instead, and truly creative people can be generated in any system, but the numbers are an indication of openness.

Another staggering statistic from this report: 40-50% of professors (appointed 2001-2013) obtained their professorship within 1-3 years of finishing their PhD! This is mind-blowing. A PhD is the entry point to the academic pathway, and in most countries there is a good 5-10 years of further training before you get a professorship. Also keep in mind that in most countries there is a tenure-track process, so you then have 5-7 years to prove your ability as a Professor before you get tenure. In Flanders for all intents and purposes there is immediate tenure. So we are taking new graduates, who would still be considered junior post-docs in the American system, and instantly granting them tenure before we know if they are good at the job, and before they know if they even enjoy it!

So that's the system Flemish universities are operating under. Lots of professorships, given out at a very early career stage. And who does it favour? The internal hire (especially those who did an FWO PhD at the same universities) over the external hire, and men (19%) over women (16%). Top candidates are plucked out at the undergraduate stage and ushered through the system. Almost the definition of a boy's club, wouldn't you say?

This is not to say that the whole university sector in Flanders operates under these conditions. There are segments that are as merit-based and international as the very best American university. There are also segments where external hire is impractical (most notably, clinical appointments). But this is a clear sign that Flemish universities have a long way to go.

Regulatory T cell mini-symposium

Leuven, October 14 2016

Hosted by the laboratory of Adrian Liston (VIB/KUL)

Regulatory T cells set the threshold between immunity and tolerance. At this mini-symposium, international experts will present the latest research on regulatory T cell biology, and how these cells can manipulate autoimmunity and cancer. 

We will also have Karin Dumstrei, Senior Editor at EMBO for immunology and neuroscience, to give advice to students and post-docs on successful navigation of the publication process.

Abstract submissions are encouraged from students and post-docs. Two will be selected for a short presentation, and the rest will be candidates for the €100 poster prize. Abstract submission is needed by Sept 1!

For information and to register, please visit: http://liston.vib.be/treg-symposium/ 

Eppendorf factory tour

As part of winning the Eppendorf Prize, I was invited to tour the Eppendorf factories in Hamburg. Eppendorf were thoughtful hosts throughout, giving my family personalised guided tours of every aspect of the company. I was intruiged to learn about Eppendorf's early history as a post-WWII manufacturer of medical devices, such as turning military sonar principles into a prototype ultrasound. In those days everything had to be done on minimal resources and maximal ingenuity. Now the company is all German precision and efficiency. 

I was really surprised to see that the PCR machines were so lovingly put together by hand, more an engineering enterprise than a factory floor. The scale is still small enough that it doesn't make sense to automate, and the desire for quality drives the personal attention each gets. At the other end of the scale, the plastics factory was almost complete automation, constantly injection-molding millions of tips and tubes. But even there the almost obsessive attention to quality was obvious - with most of the set-up dedicated to quality control. Everywhere we went there was a real pride in the company and in the quality of their work. At the end of my tour Eppendorf presented me with a personalised pipette, a P100 with my name laser printed on it. I haven't done any pipetting for seven years now, but the pipette has a place of honour on my desk. 

JACI Editors' Choice

Online here